Title: Comparison of the pharmacokinetics and toxicity of sulfisoxazole in humans and two monogastric animal species
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Permanent Link: http://ufdc.ufl.edu/UF00098438/00001
 Material Information
Title: Comparison of the pharmacokinetics and toxicity of sulfisoxazole in humans and two monogastric animal species
Physical Description: xvi, 150 leaves : graphs ; 28 cm.
Language: English
Creator: Suber, Robert Lee, 1949-
Copyright Date: 1979
 Subjects
Subject: Sulfonamides   ( lcsh )
Sulfisoxazole -- Physiological effect
Animal Science thesis Ph. D
Dissertations, Academic -- Animal Science -- UF
Genre: bibliography   ( marcgt )
non-fiction   ( marcgt )
 Notes
Statement of Responsibility: by Robert L. Suber.
Thesis: Thesis--University of Florida.
Bibliography: Bibliography: leaves 144-148.
Additional Physical Form: Also available on World Wide Web
General Note: Typescript.
General Note: Vita.
 Record Information
Bibliographic ID: UF00098438
Volume ID: VID00001
Source Institution: University of Florida
Holding Location: University of Florida
Rights Management: All rights reserved by the source institution and holding location.
Resource Identifier: alephbibnum - 000014041
oclc - 06082430
notis - AAB7227

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CY:MlPF.i.ISO OF THE PHAf:-'i.C':IC;E'TiCT ;J.TJ TO'.IC;TY OF 'ULi.EIS'3Y.A-'ILE
1:1 HiTLR 'lI]S .rD ri'J, !':-:OG.SIFIC :Jf;L:. ?EIE








B.

?P'BERT L. sUBEE?


A DISSERTATION:: PFZ;iNTED TO T!iE GFRADL'..T :COU.CIL '
THE 'TJIJVEF.T. ',' FF L FID?3
I:N PARTI.4 FULTILL::iT COF THE RK'CiUL;I.EE:iTu 5 Flr. .HL
DEGPC E OF DjCT7R OF PHIL'OSOLPI-














U[:rI'EFEIT' CF FLORIDA


10j9




































r -1 hE 1

I: r


r..:.c rE I: ,J jL,'. r















AC:I ;-,I rLEL- E:[Ef 'IT


Th aut h.r jishe e. t :-:C re- his -incare .r appreci i n .nd cl.fa d:-

cci L'r. .e:.rze T. EddJ; ; i rhiT3n r rhe sJuper' 1i-; r'' cm i-rc-ii rc r his

3j.I 1-ELanL d p 'j fl ce rcir, jr. i.it thiS r'.'e -t at i .:.

Th- aLh.r asI -is e; S 3.-1 -kna:Ji e i-,e hiel: ul .: ritici and

.i ;e ri i ,n? :_ :ir. Paul T. C ardei lhac I.:r ris si cr ie n phjr-'_a-ljcc .

[*r. i.hr C. ,,da3 r r hii C i bo i rab r E -n 1in c1 inic31 cherni~cr and-

Dr. r .,r'e Tc.r:.lar n Lir. hari" Lee f :r ch ir hs z.a.nrce in pnzrur c. -

.ri, eE 1,c : .

Lep.c pf' r[cielicn ar i special chn.s 3rE rx:pre::- J D. c r. I'rl nd.

I:.a5 .:r. 'ar .ieff, ar d rs. P Ea -II 5 ,rtell fcr ctheir 3 315 3nLe

a' ['rirnd- hip thr j :h.u[ it h in'r.'E i l. n.

The auth.or i:,:. .1-h E. chE in". Dr .i, n .-.. _':.rn 11 f r s-.

3a i. car : in th prD ra aTjir- and ir erorEE at ?ion : the ;ctar is.ti.-al

3r1al', he bil.ir i.bin Jat .

T.e i e-z Ees r ap recipe i. arid l0.' ,a-e e'.:re i d c: I r .

'Chr sl :'-" ,e- : heir u ,jder -sanr in pa ien e arnd a 1srance. h. ,ji hcuJc

rhi s Ir.'.'=; i art i-.n .














T.' .LE 'i F i:I' [: E .I








: i i f II LI L .TI I .. . . .


LIZT iF Tl .iTEL . . . . . .
L l ; F . . . . . . . .







SE.IE' F LITE T P . . . . . . .







L : j C.:e r 1: r rr C.- f ul i .... :



E _I i E:I i r . i:ru .. .. C .: :.



i-r.-.i- r Eff:.rcri of,.. r ijl y '-: .


Fharmar...kir.. c i


-.. so rpc. .r,.ace Coni canc Osi.o *.i.-.


l:cr ibuclj -n . . . .


Eli . . . . .


Flai. a Pr I.- in i.ji . .


SLTEF r -en J . . .


LATEF I.J F IET O' . . . . .


Hiph Fer zorinac Li.i.a ..dcmantraDi-.
Foltn s f i m s t: I q:._C s.'purw.= l.:-r.


la r. i :l. l .i. .


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E:'.c r a' i' ic r and [ :i 3 c i.r c. . . . . . .

e',.ct-a i:i 1- '.zi lqu' '. hrc-rnc.:, r h?:I Pr,''c dure o


1:,lo : J llp !e =al .. .

'erum I bilirubin . .

erm r.n i lbu.Tin . . .

Irum s u i :: : 1 . .

Urinar . .

njal','=.;i s of ac3 .

in .'icro Pl. 3 n Fr.:c .n 2ndindin

'.'UL. .A:ID DI:cuL I . .. .

F h r-ia:.:.!-.,ir e: ii_ o "f Sulf : ..: 3;. cl. .

Anini ..- r- ~i :,r, ."._f ,.1fi's .:-:a:ole

In cr.ra..i nou a.J i-1 ~ t r icion

'jral admini r.dclon.

A.Jmini-ctracil.r, .:.rf ifi; .:- .: :[le

Inc r "'-:n :"- -.1Jmini r. ic i

Oral : jmD-n is ,raclon . .


E.:- I,:






ro 5*:1ne .


-.-. ir = r c r i.: .fr: i, ul lr _'.-.'..js:ile c:, Hium3an

i.-.p-:ri .-.n L E r.hB Phar-ia c.:c..in : i: o uli
in DEc g b'i'ine, and Huijran . . . .

e rrum Rilirubin C-.rcenri ratic'ns .

Jo- - Inftra ..nouj: .dr-ini rjrC iCn. n .

L s--?r Adminisr.rac :.n . .

Cc.,parxis n :.r ilirubirn L."'.el ir c .s.

v'in .--I r r a ", -': ."-.; A ,ini "r cEli, . .


:3 .


: : 1 I











.:mpa rii n : l B lil rubL ir L '.' s r 1 'Si.; rie . . .

H um a sr--':ra mii r; Eic i

C:;mpa3ri : ;rin o Bi i rul.in Lc'.'el- in [.;- S ':i.
nJ H m n . ... . ... . .

C'nclusri ns .c nzernin2 2ili rubin Lc'.'i .d r.er
\Jii Tlc a ci o n Co 1ul f :'.: C-azolie . . . .z.

;c L im A.iim i r :,.-n er: r r. r i r. : . . . . . . ... . . . .

^T .I .'D . I. I . . . . . . . . . .

JlrE& t *. . I:.. L .,, . . . . .... .. .

ET:'FA, iF:.... .. ..... ..... ....... ......1-'
S 1 I,]F ... i . . . . . ........ .

_T,:,. .- T 1_ I,_ E - E .I-. ................... . .1-9













LIFT O'F T LK E


1I. "rcenci n crime-rr *-inire' Mf 3iilrcnaides; in a '..acrt
Tmacnan.:. 5I. -,5 ; ,c.tbile phase *aich a,:_.-,ate buffer ph
'.. 2.', 'and -i: thouc bufft er ipH 7.-5 . . .. . 1l.

F c .-ic in cirie inr ucur sulfcnar ]e ini .'aYaer
mecharini %''-*'. 0 'j01 mobil phase :'..lch ac-tJr. bu_ -er p H
-.)..:' an .i: h,:,c tei..fer 'pFi ".-. . .. .. .

3. F.ece iL n ime -inutes ot sulf':na- ijes in spiked human
pla'Stj sam,.pls. ir ia ter ime hancl 50. 50s'J' lmotile phase
'.i.h 3.:ecace 5..,fer -ph 4.0'",'. anrd Ji:Mh-..: buffer I.pH -. 5'. -

F.'.enct ion amr., IT nI Le.I oft Sultf'onamri.es in s.piked ni,,huan,
plaMi3a s.aMpieS in 3a ; ter mrrthan.i 60r crobile phase
-.tc'i acte. at- buffer 'pH .00. and withc.:oc bt'fr- pH ".-5 .

5. T';. e.-i D rct r pharmnac.-Lin.aci-. priimecers in M-':s
aTiin: sceret' sulfih.': .a:cl as a in.rcle ncr a'- E c '.i . . -I-

I The nE.an :ara3 on f sC l fi, :-,ac l s e ;:-.r.; rec 1 i i Che urine .: :
h . . . . . . . . . . . . .

Tw.. .:' :iomip rcr. TenL pha -rma .-.ki.rn iC p r a- :r-am r- in d c -. aldm ni -
t rEl ulf: is. ': 3: le as a sinrIle ..ral -d e . . . . .

T?. iTa.' C:nparc rnc ph.arrma:co.-innLic paraametc rs in '. iCne
a3d-inis tre sultfis .a.:. e i 3 F inle incra-en-:'.us lose

The mean amounc of sulfiso,:-:azolI anJ 1 1Ct sulfis ::.a:: Lc
h' e:.crecte in the urine .f 5 Fps as a percentagee :f
the ,0. . . . .. . . . . . ..

i..1. The b ol.:i cal half-life -,f ace -tl- ul i -.3..:aZ-:.e 1 aft-Er
a iin le c i-,e o.:f ulftis::.ar l . . . . . . . . ...

11. Tw.'.:. ... i pdarc .en- c ph a r-r :.- in ti.: pFara -metrc-rs in s,..ine
..aw iniscered- sulfiso. ,.:->'a le s s irl 'ra l ,*ose. . . .. . 5

1 Single c'-p arcmenr pharracc'kin-ec i param'7.ra r- in 6 humans
ininric redr 3 .'0 zm oral -:._e :.f lfiso-- az.:l . . .

1-,. The bio.:lo ical nalf-life '. of sulfis_.c a ..-: . . . . 59






Table Paa>

1-.. t e h i.-, :.:'i-al h alf-il e ; ic 3,:, i. l ulLi :.. :.:.l .
cne J eCl: l..:.1 CE of l ::1 . . . . .

n m. ean Jiscrib. uri.:.n :.:nrican.: j[': r rncr.a'=-.ou



.. "L,- racr.i of. j-r rit uL n *.:,r,-ranc. a cr. r dmir ni3 racr.icr,
:of ul lf -. _...:' '- -. . . . . . ... 4

I' '. Cfr.Da:1i-.i .r E hi .'.i -- .of i ecriculr.l .:.r iri ,1.. E, o s.-,
ao l lm. awi : Af er .J.Iiniscraclor A1 ;ui :.:*. :.1-. . .:

1.. *.'n.-an.. 'n f v: i :l-, :. :-. A t.ii r. i i .r : u if :-, a:.: in
S 'I. u i irij h iTiar . . . . . . ".

01 The .. i-, r :.; n : f i l i: -.: 'lJ t:l'i-Jjn l Lun i .I : oaJi ILan sI r l Jim
I, i -r :I in icr: . . . . '

i n :o n .: O w. 3 n.' of er.* im ti. rul in anr 1 L-min in



.1 erun ..:rn:eri raii.:n of: albimiin, bilimrubir, 3r
s-i f:-;,:* :ol -1 za J ur in.ar3 :aor:-ntraci.:,ns e -: u lf i:- '.:. *:.i

iul .:,nr ..: .. . . ........ . . .ih:

S r Jn ..n:.. e n.: rr r n i f l-,,jm,,in, I:.111rjtin, ar.ji
Sli .. ol anj r i c r n cr aci n r : ; E : ]
in a. 1' afr. r inc r. r3'*.eano:.i: inJ. oral of'. J;raio ,ni_ '- c,''., ,:,
-ul ::..a: .e . . .. . . . .. . . . !

Si r.i : : r 3 ns of A.r umr i . ilt ir b t ar,
iu ,l i-:, :.: ian-J uJ 'in i :- nci: ner r~, ,: i. d f i f :so':-.:!S
in O. i iArer i erri ir ij .:rj .ri i i cr ,rion o.
~ li f s:..': .: .. ................... .liJ

K .ru :on.,.ncracions or. i,: .i f albumiJ I:.Li ruti.r.. rand
ue fi r" i ..:.,;: in3 r -r r n n-cn u i z : : ole
in do:z e1 r i, Er3' -r:u- .:r n ral .Jmi ni srs ,:.:.,-n .-.
Slli .. : .. . . . r.. . . . .. li

S. K rum ..i.: rcr 1 i r .r o al -:.u.in, r il utiin, in.
al.f1 i o...: :.l and ,ju riar. ,or.-encr i,:.n :.f -,ij i'rr :,. 3: :.1-
inl di .: : af =r pi cra en :iiu- r :ral .ad-.inlS racio.:n :f
j l i :,:: ,: . ... . . . . . . . . 11

"6 xru, ofATI ..:: : :-:r aci-:.r s il '-i r, 1:, tlir l:'rtin a. j
.;i- i-_',.. :_.- inJ ur nor 7 C :- ,.:, ._ crs:-:.rio : f sA u1ifis,:,,. 1i .
n .-' :.: ipncr i-_*r:noj j3rn :,r oral di;r, i ;i ra'ij; on Aif
i ; . . . . . . . . 1 ii 9






Table Pire

-.rui ,r:ince r.: i .a-,n. otf albu nin, bilirub.in. and
jlfi- io:-'azo 3ie and ij r nar : ccnce-in racion.s of _iiiif so'.:.az
in pi,: I 3fter 1n- ra'.'ncui- arnd oral aocini StrLtion of
ul i l . . . . . . . . . . . 1

S. erum ,cri.Enc rac ion- I f a lbuminr billrubin. arni
;uifis.::-3:a ie and urinrr' ccncencrE rti.'ns f sJ:i.sc: in p. ; asti r in ri'.':eno.us and or:al admirit, L rati:r, of
i "c Ya'.i e .. .. .. ........... .. ... 1 '

'. re .i C,.n.: r-n i:ni:c :,.i aibu iLn. bilirubin, and
aulf ic:: :a ie a rjn urinal-" *.:'rrn p a cr j ian r C su f fiso.-:a:cie
in pic r .' i3 fre inrtrav'.crnj 2and .:-ral aJminir ctration of
SlJ i .; 3-Zj i . . . . . . . . . . . . i..5

30. rium ,,aun.:r.rir, ioan of albunrin, :-ilrubin, ano
asu fi .:vaccte rind urir :,ar concnrratic ns aul fiso,:-::.:.le
in pi; afrt r InCr .'enous anJ oral -adrr Jmir.ii.r action of
sui f i -.a .- . . . . . . . . . . . 1

rul. ;_errj c.:'n.:enr reaction of Ilbuj in, bil ru. b in, and
sulf -o:' a ole and urinar .:r.:r.n -nc racri on ii ul ,i:s: .:.-
in pi a iEtcr incr r.-avenous n djr3i .Jraadini sc m rain
ui1 f I ] . . . . . . . . . . . 29

.- farim i c.:rcentratn of albuJin bli ,ubi, and
s' lfiso i:a :. l an-d ,ri nari io; *:o-nc nt rat t ons of uilf i o:.:3 z:.le
CI pic 6 after incr--':rnou and oral administration .-'f
iul f i cx za ie . . . . . . . . . . 131

23. .erurm in:.-n.nc raE ions of albumnin, bilirrJbin, r.nd
5'jl f iso:: aila anLd urinar" conc'nc rairons of ,julit soaaYl_
in luC, a 1 afcer cral adminit.irat icn of ,su] if c,::- ale . . i.I

3- b-arun .:ir.cencra icns of 1abu.min, billrubin, and
s laifi o:.:2_o.e and. urinar :- concentracion; ..f aulfii; -:.'s :,l.
in nuim n 2 ifcer cral aimini craE ionr, or s lf isc z:.: c . 134

'5. 'SecoLm *,:oncen[ r [ clon of albouir., billrJbin, and
siulfis: :az: i a. d urina.' *jn:encrarcons of iiul fis.:.-' s :le
i r. huran 3 after oral 3adm nisL racion of slfii o:'a: l . . 1 5

E6. -er.rui .:,'n..-ri icrac i on .:f al3 b mini ,ilirubin. ;nd
-i l i 3o': a cle and i rinar. concencracions '.f s lfi s... a i--
in human after oral aJdmni;tracion of sulfnisoyaz:cle ... .13

,. ruo n :oncencr.a ion. of albumin. bilirubin, 3rd
uliao:.:.az le and ur- nar c.on-nc ra ti:ns o f bl fiso,:a3ole
in human 5 ift,-r oral an-inistration :.f suifisC:a:ole . . 13







fat-l-. i'j-

3 S.r'm. c n:r.c nc ra- : i:,n :f ar ll:.u' in, bi i 1 bin arid
ijd i r i- :.-..:: e anJ urinar" c,:.' .:n]en Taci n? ,-t -f i i if .:,..a:-.:'le
in hu gan 6 afz --r cr2l .dri ni-i crscr .:.. s li .t_:-.az l. . . 1 3.,

3'. an: nj : .njar ."-... r ar. -" rjli .jii l n E il
h1i rJ- r bir. -.: nj.J~l'3r b il r ii r l: 1 arn r. In i r, .:. bilirubin
in 1- 2 J 32 s E;_r iinlrj'c" n:.us .j3.TTini i- T Yi i-rL .S- t iuti ... C 3'i 13

-.,. i- n i r.,,j st ndarJ i .'iat ,n' _f .er m_ albl'pin, orar. l
l.liirul:' n. crr J za, tij t. ii irAbi r,. indirect l:1i 1 r.r bin
in o .J3.. i f ter :.ral aJminiCitr ci..n rtf iJuli -i: .'- . . 1,

-.1 leIan ar RJ s F t ai rd .j-:"l. i.-ir ..:f i-rur aj lt min. c..rCial
bilirubin. c.::'.nj :aLc EJ l: 11ir.t irn. 3an inJir- L. bIilrijhu.in
in *- f:'ire fci r incra -=-n:'.us aJ ini r .i':n *o:
l l i .: ,:''.: ;. . . . . . . . . i

-2. 'lean- nd, Er3DJ3irl J- ai i : *:' --r j, .3illijrrlr. c3i
b ilirubin :; r.j' [:c.J0. b lirubir, an.d inn .i cn-.: r i. l r lirn
in "...ire afterr ...ral a dj inin ra- ,..n :f :u fi',- -,: . 1-D

a,. r,-. anJ ic.an a3rd J .[ i : nI r' a I -lt, j i n [L.:r3i
b.il rubin, .:rnjug a t 11 rlirtubint. n J i rre.ct b1il r.jtin
in hum.n. 3 fc er .:.r i dJ, ini :rar i:t.r ,: iulf :. : ..'e-. 1-














LIST 'F .I' UR.ES


FizuJre P a ,

1. :c: ndard *:.-cnrrnc r tin :r r, r S .:,f sul anliaiiLde ,
U ijUIa3-i.-idine, brii r er :l ne s'l fanechazine. suil f3-
p'.ridine, ;ulfis1o.. azle, :" 3cecu.'l, ui f is-.,.a:oie. 2nd.
jul Lachi i ao.Ie in a 3acer, miech ana 1i 50 j.50 rnbile phase
..ich jec ce hbuffer c pH ... .. ... . . . .

:tdundard con :cncra 1 ion :jr'.'e; o i anii mriide.
'uita'u1 anli.3c, ;.l r ireri ire, Iul airme ch a ie, sulfa-
p'.'rn AIri Sul i fi:0Io 3:. 0' Zcee1 C '.EliC lfi=oI s:zoZ e. amild
SuifiaChiarole in 3 ':aterime'ac ,,:'.l I 50. 31 -mobile pha3se
:ich an iSCe cr3 bCf pH H .' . . .. . . . . .

Ca ,.i-ard ,,.C nLenIcr t ,.iIn ,ur'eS if iultrni! am i.e.
3'i'asuani.dine, F--ulf3meri-zine, ulfanmechazine, Sulfa-
prid- inre, sulfisJ :.a.:a le 3 CeL'. uli S>.az l ani
sulf rachi ole in a '-..cer mechanol I'o -.0 T1m t lle phase
cih iL ace bufSf r Cc pH- .00. . . . . . . . .

*. 3an.dari .n.:cJ n trat iion cjr c. u ares i 1 au i e .,f i .
jltr acu anc dir ne. su I f amier ai l rie, s u l L h a ii rinen. ulfa-
i ri ine .sul fi sox z le. 1 3e a c i ul c. is l_.-:a zo l ar I.
iJl ah i -Slie in a -.'3 rt. rm rh3ncl 'ou. -O l Ti. n ile p.-ase
ia hl an i. ac pH .. . . . . . .. . . 5'

i. nicrm c~ Onuc lat nins of "free sui fis:.:a:ole n *.... . . 4

.-. "er.Jm L.nceirtra ubi n sof :cre ulfisn:azLe in ,aine . .

Serum c.cn CnCa. aC i onz 3c CvisuilfilS.ds2C-le i c i Si'ein .

srum concenLratc ns Of "frLe' and s3ec.isulf iies :.:ol I .1 i
in hum ans . . . . . . . . . . . . 5*

9. ,l.n EeCrumT t i l1irubinr. roncent rationsz in ogs after
itt ra'venou adn ini tc rat io.n fi su fi a s':-. LI.olE. . . . . 1

I'.. Tear seirum omilirubir ccfncenLration3 in dogs ifcer rral
adminiz.cr.t iojn of s;ifiiiy.aole . . . . . . .

it. Ccimpari on of th: .mean coca l bil rubin concentration- in
i., s a; cEr incTra enou J ad oi r-al :Jiri l t '3 ac in c
s l f i :.a ole . . . . . . . . . . . .






Fi are 1Fi :

12. Co.ipris. n 15 o. f c e c-ean ,::onwi cnr r..,d vil'iciJ-bin -:on:err: rjat i ns
in d.':E afcrer iicra"-rnous and o ral adrin itni E raci.i *f'
a' fi i i 6 ':- : Ole . . . . . . . . . . . .

1. Compiar is or', hr re r indirect ,Diliru' in cio-n.:nri[r Ei.n;
in i:' i after incra-Er-.u anj r, .:.ral aminif :raC i,o,, :of
l i .. . . . . . . .

1 l W.l .n rrur i t iiru'i4 n .on.:Ernscr c in.s in s inr; jkfvr
incr '-Enou adjmini rat :ion ': of ulfi .-. . . . . . .


ajminl3 racior.n or.f ;ulfi ,',. a ..:! ... . .. . i

Ir. Comparis.:,.i o'f the mTrican ca:'ia1 c;i irucirn .:'onc ncI r3c:~3 ian
;'winLe aift r intra '-rou andJ :31 .j3Jirnis raciE : o:f
1 u.. lr l .: . *. . . . j. E. . . . .: . . . .r

1 i'.omp n :. .. f: ch r. .a c nju ace i ir t ... ric.. i. .
in i'.ine aftr intraj.v=no: and ocal adminirtracion of


1S. Co.m'parison of m wer an indirect i lir* umn c nor1c1-101 *i .:ir.; cr :.
in 'rvin- 3A Ec:r in ra-'ous and *r1ai amruniscrac :rio :r


19. .learn -erur, bilirubin .-ono.n:. cracr jr i.on hi L ann ;:i r tr




*i3': and' irnr afcr r incraE'.'inou admirnist racit:n :A,
S, jUf ;'.,..r :, .r ....................... '7'
Su i fii ..: O. le . . . .. . . . . . . . .

"1. C:.-.p3n ri on of chE- -ea c:c l bil"rubi n ,: rr11 rb :. 'liCi3Cl, 1 i
1 :' a3rd wi n-; 3ZAcer oral aad.irnil crart l n ot ulfi!- 3 :3 1 .

-' ,.:. 3ri1 .:ri .:.-r 1e r-ean .::.fn ju -.J r- lilrti r .:.,n.:ercrati:ns
in I.:. and s ine aft-r intrav'.''i3'o admi; nir rici.n .-.f
Ssu lfl :a . . . . . . . . . . .

.' C mp ri o, '.:n :f h- majr ..:nj'jg 3tj c.ii ru'in co.: : .-nr t on





Iul rf 3.:. .. . . . . . . . . . . .






and :ral adr.inis ,aj .i.n .." ulfis.::3 .l . . . . .







:Ijurc Pi2

fer E r hrrmi 3lhuiT, ri r,.:. nc nr. ra i: n L in :;. ne tfr-cr ir Eran.'ncuiI
and .ral ad3 i i c ra i:.-i om Il fn :. ara J' . . . . . 10i

-' .. era al3 u'-ir c;.n.:ercr r t. -n_ in hu,- in a cr .: r
.ini r c rac3EIc- .i- : -ulf1 i c:- c ic e. . . . . . . i)1









4 t z r.ci"'.C [ :' c rE r. i-. ti[rE- -zr' r-= D c he r r. 'h. C ra-.ju t Cou.r'n.il
of er iUr. ir1 ; c :D Fl.id in i' P cr CL 1 I I. Fn t 'r -ur ; re n E
f'.:.r the De-t r f .i. cir .l P P r'i-: .:.-.jpr



C'tP.F II ,ii T HE F'PE'JL'L I: I .HLTTI:CS 1'II T''I : Ii i' F lrL 11-.iLE
IT: LlL-i' .J i,- .i p 1. J, G.-,, T IFIC 1. L P .: iE

,..
B"

FOiE .I L. IJU2EF:

-u1 u 1 1 '

c-,lrian: ..:: T. E.j i
:t'licor L.p [rtm r. : .3intm l _-. t.'iiir:e

This c:r. i-_ rl. t i -i: ri4 ,' C. i' d*i.; ,L p j li p rf,.:c-, .: ; IL id

.:ht ro 'i _r..:,"t'; p-iF : pr ',.. .'ura e f,,r s_ a, rjr 1l0 ;nd j.icau ,i- E E c .c"ni :, uli ..:nir- .L ,

e--:pe:.i '" -_j.[it "~ :-:,-c In. t ..ilie a.n.j t .:. iu a : .h-

: :1.: i C nd t'i.1 '.:ret '..: -.:, _.'.:.-:a..,o 3 "' tr. ..r- ,: :u 1 ul. : r..r -

r ii Tr.: ,:- .- r. ,: :-pc .. =- ,r h uM]i :.3 : and :s'.:. .

2'jse tre. -fr lo' bnl1 2 . ni4h prrt.rL;.n:c- 11.Ji:
-' .r. 3i,::' -'" e -, C r, 1.:L ; t"e .ina l, :if r .ijI p2 r [ : r.: i l. a,.J i -:




~l -.*u id -], i -1 :.r.a ic. i. r 3.-r.cc in: Lu i r ri, in i[' : -

:oi c ..: .1 _i i -:- :.,,J. :1' jid s 1J fi thi :.ie a r mr a ,: :. :. ri.a

pr, c : '.. [p'.i-.ei t- r r s_.a mipl r, e r aJ '- 3 :- i.n' .:c r 'U.'' uE O.rt.: .3


:nd -p l, '. .,]: /I'- n -i a tr. :l - c. :.a ,- rr : ,,; .: ,i r -J -= 2 '-.:- r ..rin c tr' T i',e

tn,.t_,, '.: ha'-3 :.*is -J.''- d.-. rLe-, usr i.ed "=Ct r .*'.. "iec.-. .n'1 ='. PH -.-5

S:-" :^: i pjparatcion -':ld ljuinc1lt ci r Oi -r l.: f j i a- i id- -r' -:-fi 'zj2,.3r-.il-' .

3- ., .-chtp r Ca l [ nar ie ,-' d I ,', 'l.' -: jl.e- i : l i pe. a c e -.J 1.


,r. .ch a :.i ;i : --. -' : t L u r' CH -. 'i" -,. ,.- '. : :- .i i1 3:,_

-nj t;.: c.3 jL .r,...t [;-ir, :. *: '.'.. 0e ,: p _-d '.-: l. ,ir. ni rlin. f ::r ,:.': n-

,n.: ,i .- ':'. -' "; .... J : o'C r, -ted .LL. r, i.-- l-i ,c I 1 1 :e :re :j r. j '. .'..







or filtered. chrou, h 0.- filters :; ith.ouc loss .o res. oiu i n. Llrinar.'

e c:ra:.ction of sjl fi :az:Ole and i c 3 mera.. ite, cer'.-iul is..:-az' l I .

invol" d *:,cd ing I 5. 0 ml .rIf urine c.: r',l acidif .'in tC* pi ?2 .30 ''i h

:.en:encraic h drc.jih lorl.: 3acid an ext r c ti an incco .:hi rs.-fr rm. Ti Tc3

erTI in rn Lrnnr" Iflr Iso-xazol .er e C~e-as inred by ..illing che a: id

n .r.:l.iate for 1.0 hjur ac 1i0J "i and perfaorT-in.g he respect ,r.e e::cra:-

1: n anJd Separ it .n ce :hrniques pre i:ou1a i e -cribe I.

SL' r ir.ndi di5Ju i fro.:mi each pec.:ie sea ere .adjinistered a slut ion .:.f

ulf .is ..::- te aft -r a 1 --h.:ur fascin. per iod The rial 3 :s c ndu.:c e.

over a --n.ur peric. afier in ,raen...- adminiat ra ci:n anJ 3 '6-h.ur

peri-d aLcer ,:ral a.ministr r i.:t.n in do,:. and s.,ine rand. over an .-hour

period. after ..-ral administration in humans.

3Aal3 s i ,t-f the Fpharri.ac.kineiti. pro.fiil s of c 3:h ap=.:i sh .-.1l

rhat *,:Li ..ere -re are sFimil1r co humans -han sa;i:: e. d:ri.- :er. d-iferences

d id e:.ist f'?r bi.cil.: icai h lif-1.1 s. distributi':.n ..::.%nstants, .-lume: ..:f

distcrl-uci t n, biWs3 a3i 3abili :.', miecab.oaisim c r,- me 3.:er:.i ,1'. 1 ) .aeri',:3tie.

and urinar'- e.*.:re ion rates am:rn; ll ". spec- ies. T. r al and -onjuglated

bilirubjin sh,,ed smiill but s[cjri icall', signifiLi nc increases o *- ..01,

in |ans after :.ral and inra '.:encur 3dminiistrat 3 n i .f sulf- .::I :azole

*100 nO .k '. i and i.n '.iine 3frer :r.-l adsmni tr at in f sulfiao:.azole

0 g.'ks The p.e nr ill-: co..:. indJire.:t, ,r un :onjga:e bilirJbin

Shc e'. .i d smai buc s ca:. 1 ic ally s zinif ican: rp -: .01li nc. rea-es : In .J:.~s

afrt r .ral 3ad-llniscraion Af sulfis:'.:Zle. A similar increase ua=

co'er'.'edj i n s':ine :.r hulnans.

IT:. l and c..:nju 3atred -.111rubin .ere si.gnifl :antly Ip (p .01 correlated

irn. s r. er :,ral Ind ir'trjven us admini =:rz. Lc n and in suw ne jarer ,:'ral

adminim t ra ci n .i sulfii soyaza e. The inc rea.ie in cni :onj,' ced bilir,-'ir.,






al .--n: t.Wich .a C- n.: :"iii- icr, .: .3:;.e in t:., al bilirJ in. c:ii b .1,u to.

h--p3c1: Inc ir.: ,ci.n .:.f zluri r.:.nidA3r. iC c 'ap c' .:r r e:ur2il r i .n r_ c ..-=

dji.:ace, ol D i r Oin r.:r l,- r.17:ipae. :. "C l rie r, ":,2 rEcc i n in, C: h E -ih.

Th r,- .'a & ; ,: a 3 ; nit i i-i ne ac r.'e c .rrel ci.:.-n 'p .01i n c:n-

Lu;jC1 n.j inJ i.ire c bilirt. in. ihile coc al Itii iti i i i: r in

,:3: f rcer *-.r ,l jnc inc ri--enus. 3.jr ni cr ta -:,n .:,f :ujlli3 : z l j _.

I z: )ppj _r c*:, t_ ru%..-r sinilir c:- I-hiumiin in rhe pharmj .4.in-l .:C : ..r

.ultfi: :::c:i:,. an.d che Fp.:*cpc. Ci l c:::i c: '.' ** b il rubin uldj b, :r Te3 C.:3

in dc' The I E -i in ln i lre c *r *i n .:.n l i: A eJ bili rubi 1 ij. r -.,nd

.n s ,p- i:- .ii -r. -n c i ch J: r.: : i n I cn- ,i.:. .c ai -ic .and :.n a

r..uc- :. jimi ni: Erjcicn 11 if r-_n.: '.ii:h r che .:rll r: c.E tb- inL ri:r- 1ii.:ci

c.:- inrdu,. c r.:.:ic t r.chan an incr j3 n...i l 'r:uc5 ,:t" ,,f iini cr acri,.-n.














I;T RODL1TIO.


Eilfi :::a:.:.ie, a pNarna.:iuccail aenr. regular i used r u rinwr

cra.: ilfecl.ci. n l ia: be .a P ceriaill. tC:.::i : *:Ci ''rrpouni d jd e C.: e incr ea e

in serum hilr bin le'..' :c a icer iaminiscrati .:n, has che p:.rcncial f:r

induc:in- bi:reri3a rii:ri race due co. iong Cerm. iow, Lei..el e.-casur-

c ir.:c 1 che f: d ch- rn aind i a p:. : ble. er'i.-ircrmnr al cc'ncamirnnan

especially' in 'rban uiage. In ord.r cc ea'.'3rlce Che a s rpcion, di;-

crib c:rion. r-A lb.:.i- ri, and e:creC cio:n of *5ul ri c:3 e. I c -ai n :ces ar

r.* cC abl ish che pharmaie.:kirr.e ic paratracer in tumnan and animal midel

-'Es :.:3.

This riall v.: t,:. 1) find a rapid high F erf'ormance liquic .:hror.acc-

zrhici.: reach.:;d f r d ecrc: in ijlfo Inaiide;, espe..:iall..' sul-i; c-a:zole and

i mnecabo, lice., in a iol:.:ieal iari:. rd 2' ,: t : co pare .he pharn~acc-

: in L .- C and pO.:rencial tm:.:,: ic of utfii .:.:: 1e in hum-ans, ac. ,, and

sine in order co define a beLcer animal model cr. correlace .'irh human

r s ar h.













iV'.t'; OF LITEP..TUiri


ihe rie ic l and ,u:L.1 n.Ilth i p, E rcjr.a..e f he i- "-**'er" :.f :,ju .,:.f.3-

milJes j rihe fir r i t -e .:hlu ,.:c rn rapejcri: a nc '-as re li.:ce.J t a

ujJe ,s.:l nirne in mor, bi.11t" anjd -r re rlit .ij E .:. inf,: r .:,iu W .e :i i. i

FP* ul Ehr li-r., he f3.:und r o:; mo: ri cr' n .:,er. h. jp..r ". inr i. iw e rci- el

:.:n.:epc o:f re-e us ,:[" a-: : ,e a; of alu.cihu. er iai a.z. enrs 1i -2 1. Eu lf -.r.i1la3-

ile I an3i ri.: en. r. ujir.- i.amij i fir i r- p re pare t- il .:. ir 1.:1 dJurin

che inrie.'ri :aci on 3 r 3 -e .A Jru; uE- pfaE-r ';a s F ueJ r ['arer

and .lnczS: h I- 1' f,:r Frrc,.:A1 3nd tCh r 3:.. J as :. c aniinin

:uifr,-nan miJ rj.Ji.; al. In ~e r Ee "ear, .- nn .. rl in: ich .larEL ra

a!icr -.,: o:t r- ed r ac mi:. in t[' ; :E E;ic El repc.e --* ,, i 1 L a. r.eri .: :u

-e ,rrc.:c.rece t:' pr.nc.:;r il i! i, s .

Ar r.-, F ja s jr Ir itrE rcu e. researnr.ers fM:unjd char. 'he :.: i -'.A e of

PF'roncilr. ;.a s il in --1 .:. cr. **ie i.1 r3- a- r: b.-nb -ria .i, 1[:ijr..r' : '.h ich

,i. cri_ : o he ci ch e a.cc .heml.h. r A .rjp jr i. aer. I ,. Ci.:e brro.: k' .n

v'er.nnE;1!' ani LucL.lc or Wl. ,l i' r orc:r fa .'..rablt e .11 :'.:3 re-jul]c

.icri Pronc'i..;il ;hici:h pr.:' ed cr.e -cnE i : .: nre chnar -.500 julf,:n iz.e

j ri"a r- s in ci'-o iriE i rcj : b i. _' 12 .

;lThe i-echi, j iof 3 r.:i n f sulIf:namiles ii n Ks ed cj n e r 3t .: rFpce.. inc.:

chc t.a:c eria1l *ell in ir. r.:.n-- .:.r.i.:el .:r-. -'r.r pa'r ial pi::.:,:i arc r.

iS :comrrpF ce '.iic. i r:nized para-a-i.r:.teni: i.: a i-A P C -. Thi .: : 2 :lD ic

innicicr caccer. .al r: gr h' .', pre'er.rirn; F.j.I fr.rn _ein ; incorp:ra.-.

inc: p.Eer,:o'. :a l mic: [:i i .: a:.di ci:h i: relu.i l r.: c -:raur l.'d : i.








acidJ, *3 a Coin2.e e-:en-ial f:r carbon i ec.a lism I1'?, 9 Although

inhibicti:.n of prerO1,1:'l tlu3-nll m ac.i.j sn.- hesis is in~a 13ceat the efecr.',e-

e; or sul .nanie: is, re tricted t: b.;a ~cei:i3 which require .:'r -.ntrineslze

pter:'vl.1Iuca i- ji3,- j JJrin., c ie ;r.-.rch pha e A i1o2 pha-. or iscent

peri':.d. which h is ies~ r-min-d .: ch' *:.:n:entra i n .:f sct red ptco .'1-

gluLai-: aid. O.cc r b ere'n he dninisc rac i3n sulfonamside iand ic

birct ri.:.ta3cl erff.ec:c '2'.

The tcruccijre-3ccti" It rel a ,in-hip o f ulfon.miide: i;s such chat the

Fara-aTin,3 ;r, .i i c .I e:i-ential and .:an :nl: be replaced b .' such

rd c i iil- trhtL can be c.:.,rerrted in i..o intc a tree ar in- gr.-up. The
1
--'O.,rH. iN roJ p i5 nor. e: i r.c ij. t.c rche linr Lae- L ..C iulf'j dire-:tI '

r,:. the t. n.'ene r in ii citf ici.:. c ilmportance m rhe nim re elect ro-

n. ticl" tc -c a -, group chc irearer L the bh3:eri-st.- c ic i cci .i 't sice

che i .nic: fornT 1 T.-.re acti'.'e chan the- molecular form ,'.I This I'n:.- leJe

ileJ to che earl. ;.-rthe~is .r ': ia-t .'::a:-.le b:. Heifman-LaP. che in 19'"

1 :.21 -nd its us- paicne c fo'r 'icrobial infecclon i -in.-e sulfis_'::a'zole

i readily i:.nizeJ and e.c.:rer., b, :1,:.merular filcracri-,n, ic li used

prrimar i1" Fror ijriri,.aT racc inrecir itconF i'n' .




iul f i :-: : e


The thera.:-i; c in.je:: : f sulf,,naiiiies is reli i'.'el: low so cour.plece

bi a'.'3il3abilitr- is important to Tma ir ize [he percenc:a:e of p-jcients wh,.

1ill obr.ain a fr'.v'/cjbr e Cherapeucic respo'nse fci_.m the iJrug u .. :. ult'i-

e-'oxa .le :.r :s, l iffur zole (3.- .imei ch .1-5-s-ul f n lami.J'-isxa.ole'. is a

hite-'ell.',:,in, od,, rless, sli h l-ti bitter, cr:'istallinr e [o'-.:der ,iA h a p .

or -.9 32' 1s re ati'.'el.' no ,n-c:.'.ic, and is bl- co c.on r il e::.peri eTincal








t. ccerial infec:t I r, n '- .' ic i dit riCoutd in he e:.crJ.Leliular fluid

anj rails ci en: r .c lls 5: Th.-r.frf... c h,: a inir i rtr; :.nr :f

ulfi: :a:3 .:.le re ul it in a cl -in .::.n.:1.n r a l., .r :ni h is nt, ruc iElieS

hi cher clh n rth3a pr.:.1J.:ed i- F eqCirl -;Jil-ic .f njlralii ini e. IJ .




El.: J Ci'ncenc r i:-n *, f iulfi i:.:-,. le


r .- i :rj :. i 3T jam .:okin cic I _cuJie in Ji-',. ',,ine an j 3accle :.rl,;

j.er rrrjin-.a; i -i i,:.J I:.' i "frT'e ,,i .u ulfi co e 1 1 .

In these e.:.-rifnc-, l -e 1 .:an 'r l:,.,jj level ... al higi r.:. c,: h:ur.- atrt -er

:ra l drinis ra3Li n. in : ini:al rial- .ich ..:'- i '=n '. '? c: 2.. 3

;ra -" -1 er J3" ..rr'l ,i .:i: r..,n hl.:..::j '-:,n crEn a.i. ri, 4.. C3 I .0 u,.' il *

l-.:..,d. n E ra inei J. Inu riv'.'no.u- 7dm inicrtl*ln EZ c-2 r'1 1. .''r.

m .. d,'. ';e -i r. I re resulted i, "'... 1 _f fr-e Jru:? i) O ,- I12-. a

I -, ur in d: c.;; pnr:,,u-:ej .? f rreC J rii r.'1 0 i 1., .1 1 i 1 ; I

a.-d .r9'.- m~, pr duice j .? rg :ft fr-.e Iruj '.'' :: bl:.:. -. .' j-: .

l.,b :j'e..,is Jini rac i.rn t: 1.:c:s i" r i SulcE J a e7::Lin nl:. :.d

.-:n.r:,n ra ion hour- after drir :ni crack l r.. mini '.r ci n 1 ''-."

, 1' n.:. ',,'ei.' t re lce. in 1-. -, .:f free i rui .I lO i :l n1 3' .>all:

-13.r .,.. '2 reui. ced in iJ3. m. : f free dru
-rio' ff -. :-t :f s=.jlfi .:--.:azole c: : 1 '-'. :,e ulc I a pei i l

pliasai l;'.el .*:.f 1'.. m Il' ,1 I c. ';.-:.lie ir :.- d.

The inil ']Tin;l craEi,:n r.e :rced in r-ine 'I.:3- '.i intra3peric.:.ne l

inj -: io 72i '. IL ~z.i. p-a .' bl .I?.:.J Ie'.i . : .- free Ar !0', nil

bi ::- -A i h: ur fiter- re :-.: -.in a- .-se :,f 2'1.5 ,, 1 ."d ;.ihc .

In J.,-'in: ,_ ilJren '" dni inliscr.-Licn 'f -ir'. .-: :,rA l *:'de :,f

') if e L. b...d:- ,.e :l r re -uir jed in I'.f :.r free s,' fii.-.:{azol.-: I.L."' -,i

:f ;eru- after hours nd J.. mg 'i00 mi atrcr 1 n:'urs. srn ,r l dio:e








j 1l'0 c. g.':vz result! Ced in 9.2 rng ,if fre e ,ru;,, 10 m .jo ierum ar 3 hours

and 2 .' m IC, 1 ml at 12 hou-rs. i.vec e' 3l. 3 5 I ,i.b ,.rved :h c a f ,r rial

In;.eci:n of a single .0 im ral d-se in aduitc che iean .io j c.,ncen-

cracian of free 1l fi.,.:a.,e .1 '-i.0 'm.2' 10i(i i .arndall e al. '-'Ia

ad nin itered .in oral dJose of 21.0 gz.i e r:: h ours f:r *:.:,ses3 o 6 adulc-,

..hich pr,.j'uced a mern blood concentration :,f 21.0 a~ i c jtal sulf1 z-.:-

::1 10D0 .' l 3: 1i0 hours atrcr che ini ial doJe: he free =ul fi .'::. zole

z,:ncenrracio':n 'j3a 18..0 m, 'i I0 ml ac 10' h uirs Lau r t ii n and Ilullin '-

dose.l 5 aduls .rall i .'ith '. or .' .m on f sul is-o aZcle '.. h whole

o':o.,J on,-entrarci n :,f free sulfio:.-.azole of 3. a- nd 3.r mog, ac 2 andj

h0,ur respect i'.eI., for ch. 2., 1-i do-er; the -.1. o. do'e produ, ed "holi

bl..:d c:,n r enr. ra E. cn. :.f "' and -.3 m ac 2 aid hours. r, p-,: c -.'.t l .

BP. 6 h.:,-ur che conencrac on '.a- 0' hf t he hour le.el for bocth che

.O) and -.0) .m dose and by 2 L hour z ihe blo:..d leave. l had d C:reaneI.J r.) 2

f.:. e h.ur- .' : d ro e and -2'. of o ce hour--. cmr do~ e.

The fir-r complete phLarmac:,.k'ine[ic profile in humanrr:s *a cond.ited

I:. Ilaplan et al. 'n'i Seen health r adu t as ini: cered a '.) em ingl -

oral d,-e '-id a mean ab3h rpci:n race :onr r.canc :rf ,ni.12 m 'hr hal'

lif :.f -'.- hr Pne k pl.asm r i e :.f 2.5 nr icth i .- .2 ml. !rtrav.enous

a.iini s cr in .:.r a singlee C.i) r m dJoSe [t the same eluncee.rs re-ul:ed

in an ini ial plasmr c:ncencracion .f 25'?.0? u mi a3 hali life of

5. 9' hr. an.J a .-')j urm e .:of di-tribur.ion of 16.3-" .,f bod'.' 'si- hc. 'rne

11 dirf er.enr suifi f j:- ole bl-.s 5,,0 ol ere a imini. cered r.,: human

.-i~rnceer (-'9 i he peak pi ar.a leiv.'l '.a -5.5 t c: f'.5 u., ml in 3 hours

..r les; che hair lire -wa;s .5 hours.








*!e1c j-,:,:llJ O.f jul lsi .::3 :ole


_,tjrable firic -pas :onjuiz3ci:n of cte jrri.ajci: inp,:, ,roup ,i

o:f uiriio -:*i.aZ: l- occur .JurinL che inicl.al passage 3 of1 chi drn ftrom: che

zaiscroinc3 e1i,.al l.ienr chrou h cthe li'ver fcilc tn ,:r l a.jir ini5;racrt...n.

The : t.:rinr of ':inju :in.:n i .:r-i-3se is chc orjl J:los .*el:cea;s .i. :h 1I

*:.on is;cr nt .ich a er ti rirSE p. s5 *,:,i j ,j Ec Thi d..;;- rt,:.L ,:.:.:ur

nich incra-&.':enou. a iliniistC r:-tiln 'Chich inricaitc.s chc idose j.ependenr .:.jr-

iju3ac i ol:icr before chi r Jr rt ach.: the sEir.*.: i r.:uI alor.. b,

,nhiLbic irn ;he -ic r *:ci-i c,' r che .tooi a:h ian, 4,all iri es:rl ne i.-'-'

JruJ at.bsor-c iOn, .. ne 1i -= i t e to in:re C,:nj .3 c n ol he .Jrj i .

ie SO1 n and 'J F' ill ;.' rep rcc chic Terani half-liei for r,:ac, r 1r.ion

, che acec conrju'; ace fro sulfiE ',3.:1 is 30 hours'. The m haif-

life orf the ace l .leri' 3cr. i.e -; '?.: hr hih -as ![. er crhai ch hal.f-

life o cf tc, e rern c r.poujr.j i".' h L u I2llir arn ::jl ir, ,-.' r, p ,:.

i-. : of 2.0 n -i .' ,m oral j -': 5 -er' :onj ac-r wi i r.hir h.:,jrs 4hile

.'. in C.in ,' rcporc.a s 3 c ...': 1i. 3iCcC"iajc- .

tWhen a.:ec1 l II i ul i *:.:*:a.:le li .a inIc-rE-J o: allc the en -s-.c

r;=po. -ibe rfor : i con jZa iorn ar sacr. racej -o frt r Elc10io met L.t.li :

to h" -'. E r .r.i3 .' d B-e 35 h or 3Cch- i [; 'i L i r ;'*ac*.3-

:ol- *.oce inC:reaSe i Flat e i i -'1 suppor.cCd ChiL Conepc t'

rep orcin. 15 o: suiriso':3l: e is r in the [i -a.ecC'.'l ac for-, .;h n 3a:cE .

i i sulfiz,:,;o3 i j.jdrnistere E1.1; 03 i i j si* :e c chac che ah.h

Js:r;e of prccein bin di; of s slfliiisa-..;e ma; spre it first pi'ssa.= e

rErcjboliF c.. che It 3ace rir.'i ci'',. le3a'in, m-re of rhe [.a F r.-nc iru

r 'ilable for ics pharmia.:ol cl. :ai accion.









Protein Bindina of Sul fi,?:..az.le


ihe binding of a cru co plasma pro.:teinr affect; Ice acti itc', dis-

trihbuc1.n, ractE of metaociism.. and ,;l.-,mierlar rilcraci:n n 'i fhi-

de:ree of binding i influenced by nte .m- lecul r ;z.:'ucLt re o.f the iru ,.

Its lipid i:.lut.ilic., p r' rhe *.:'.nr nccr r ti:n jnd inic: fror plai.m

procreins. che number ',fr bind-in- sice;. c-e eene essence of ,competici.,ely

oinrine drugs aor *enJ'c nou s c,..ompound and tch physi:jologica.l o:r pacr:c-

Lo ical Scae :[ the Sjbjec.t i ', -i, l- 50i. The degree of protein

oirdinc increas-3.es near rhe pk i11. '.;ith a laoi (acidic, pT. a hi hl

je~ree of dru- ibirnd ine occurs a phy sil CicalC pH while e uniuponi-ed Jrus

.are -liehc!y, bhnd. The C.:njat irrn of miechtl group ''11i increase the

binding cernden.i. :f a druj ''1 .

tiLtumin has a zreatr bindijln e effect .n -ulfis.:za:olce chan alpha-

or 'armna-globuiin; ,1i0'. Experinencal binding rof sulfi .::-az.le in v' iro

S5:; albumin, pH .-. r zC', resulted in 9'3.2. -1 bound, 1.8 33 free bj3e,

and O.iJC'L. free acid i .I Jhich is e.:p-e.:zed since sulfisc::a'ale ha3 an

acidic p.3 and 2 meth,' roups. [n .'l.o e:..periminct in hunans resulted

in approo-:: m tel.' 25 ,:f r.he ral jlulfi so:-:oaz'le bezin bound cc pla na

prote i 1 -0) The pro:cein bound :fraicti.:n .:r;s a, ; a reSier-o i Decr.e n the

Ire effect e -. rd to:.:ic l .Iel of the niolo a call. j r-i .e, ujnbcund, ur-

mecab.lized f rracciIn i bhuE here appear cto Dc no correlacion be.Lcen

thc half-life inr main and che percentage *'hi h is protein b.:und i'-2.



Toyc rffeccs of Sul f i; x.azle


iulfonam.Dide5 as c;l.as of chermothe r.]peu c iaenc; are considered co

be ro:.:ic due co prec ipitac i.n in che kidney, p'uduc ing cr:y. c.-illurria -'i i.









The inrrenr," of reni.a i :....i.:.:-is 't:r aliri. .' f u1fi:. .:.:,. e ir .ue

cr. e e..-: pc'nal1:- hi.: '.jac'er -,:iut li i ." i che fr'- an i c i,,n j .ii e

i acec-ll fraccl..n: .ic n Ch. ph- iC.- -?I.:i H ;,H ranze i

inic r: i: icr i-- rLi'.e .een induJ :eJ l 5'j c 3i c-: :.:. i- C: 2 E Elr i n f :,r

cie e i [riniJin,. s it: r ar tirir i ,r a;rd jr.:.S mtJ i 3 in r u i

.',er,,'.li c, .: nemia ,e r-, -, ,- -r- .h sp, rLc_ ,_1- h,'.ir ;.:eni:.e de i,-i n.: '


i .lJ l. inhlit icl.' [ anrEi,. ulanE ,cjr '. 1 ri ,1, hl p r' r-''i k"ic i

anr:re:' ia i i r') ,_r.-i.nul :,.: S"... ir. i .i I apl, ti -i u r il I-'TII i. l 3_ i-Se :

r,,r.':c.; r.i ji c ",' :i i .-2 :cul i[ -. :-._ r.J '.'i ch c c,: in,:,D i i -4


f.:.i .'in l sal tfi .:..--.z i chercar i .

I' c:,n] 1i-') ,- i lt:r-cir-cr rac ., lar i-: c c r :'i id -. l ain l

:.i: rred C.c. i c i i. a -n.1 1. ;. jij i :,- :.i- [:.ir 13 -' e [ '.: T. he i

r c a did n E -:. 1 1C 3-. : D .ra n ini r i .u ri r an l.: c :' 1 r

3Fl i:,ri anem i... . .. *. *[ r.I-r .a c. A- d-ia..a .e 'ri.th race ~c-, as-,a

niti e t im :" .:-ll :.cujnc an '. ii r ii : r. c i err j I 'i i. I i

iecrn3i ].,:e for i'" of -,l.:; ce s. .. I LIJi'.JI :.> I1.'.<'. 2, I .:.f Li hrr, Lu an.m

c-:.' ium J T S le I'w. T L 'i) I .:.L r inirra 'ein.IJ.fl s '* 'J3" -..: ,Ti : aI' .1

i I- i, :r cli iCr-i a3nr :.-d iy a 3r i s al re -:r-.ci e ,l ch- sutcJr.,uI -

rcucte *f 3. ii. Crra l n cr: 'c an Le.-') 3r. .,) n.j -. 1 2 fi : r. c Lei

l ichium -n, -:. ,,iu 3 ir, re peccr i l .

I'e rnic r iJ: has L erni r.ic.,, cre .3 in i if ir ir.: a:-- l-i.' :

-erj;-a bh i rutbir in .rer, acure r, fanc creacedj i-icr .jl1 :s'- .:le i "'.

5ui Ierni ceru: .: -u-vr r .hen ui-.:: ri; r-ad or i .-lire c :r t. lr jbin

..a ie.: Can a2 itr. a r in rin -. I.- chin 1 .-'7 im 1 r inf3 r.., arid

le..s crn 1a,- ian .i hnfanc iThe-.e o:: rren :n: ,ere enh1nc:e- b pri.:r

acia3.:.i r, e r.:;-.iia. r. h'. p crtier-n a i .








FlaPis a s3iples r f:m i adulr i ssbov'-d chj: sulfi -:i ,:.::, Cle c:ion(en~ n at.n

abo'.e 5 m.'11O," al had a sienit'fi. nt *iispl .inrn jffecr on ilirajbin in

icr: '6 '. ulih n compared co the .Ji i- 1 acilnC ffe.ts Cf sali,:"lic acid.

sali.c::1Jri,: acid and isoirirn co sulfis.c.a:az e at 10 n,. i'"I -1 concenrtra-

.iicns, the most pr.onicnce d effect: was observe J when sulli;so.:a:ole *displaced

bilirubin from plasma samples .-f i ajdulcs and 13 inrfants in v.icro ,r. .

The dJi pl a-emenc bil rir in is due lto :ompetit icn for similar binding

sites on rhe albuain molecule i3 ).



trinar. E. crec~,i.n or S'ulfisc.:::a:.:le


iilf s::-.:.azle is a c:r. c ;elv. secreced in the pro- .mal renal cubule in

dO -. and humans. Tubular renasiio rptior is a passi-.e process -hi.:h depends

on urinary pH i.i2'.

After sinrie doses of sulfiso.-azole. R3,. -as recovered in human

urine '.Lrhin 2' hc.urs while .5', :as excreted ithizn -3 hours in dogs

I-0.i. IKaplan etc i26) reported i3 Tean of L2.? of silfiso::a2ole i&-s

-eco'.'ereas the "free" druu uichin 4a hours afcer 2.0 mi intra..enous

Jos- in humans while 51 :. was. rec'.ered after a '2., nnm oral dose. The

cocal sulfi so:: :Z:: recovered in -3 hours -as 91. . anj 9B'.ij fir tne

2.0 -m incra.'enous and oral d.:se, reT pectr.. el'.. A'elnstein 1'53,1 rp.orted

2'", of the lf le creed s in he acecylated form.



Phar-ac.oki ne-icl.


Fh-armrco-'.i.net cs has been defined ,a3 cte quarn.icaci. a stau:.j: of the

ahsorpction, distribution, metab..li-sm, and e..crecicn of drarus and their

phar-n:aologic, CheripOucic, and coX.-i responses in animals and nn i21)




- I I'-


Thc pLr-F.- :*r rh:rr.-; :..i:icrrc i re F.:. rcducL rhe T rheTi a e i.i 3i.ac

. .:1 -r.e. f r:. ar, .:-.r ra n r_ :. mer ani.r a[jl r_ racer i .'hi,-h Cai c. e j-

c.c T- ile :. r.:-li.c i.r. : .*:- :h r-'ulc r :.r i uri re ::p: erii- men r ..- r ,:.f h.:.i c

-r[ iE. "hl -h ;:.ulid t.c r.:., r rii C *:*: *U1iin2 anrd *:.-r? L if .a rrie: .*: u

irdl i, Ji d J-4i I' .




. h 'b .:. r- :.n Pare C.r:r r. anr an L .. a n:-.rli l c 7 1 "



Thr icre[ : -c er t iorpci r, r ,:nr ne I. a j racheriat ,,:

:-ccrip[i.:r .. .-[c r3cE i hc l-h ':i- dri'u rec.h- F [.ie :'Zeni.ral .: ic: i .:.

'- C'Ti r t E.iri E Er ii- c .: r'- Ti-1 arir' h. i. ir:i, ,-: = rc rjE , Cin-

c r i :.n i." i c j cxime -.i r eq ir.d ir.h 3a :c rd l.:r :. c ,, ..ir

"-c r."l d h ', r, e mI- h-,*d --. i' Th'C i -lI 'c 'i :,[ ChL 1i iil_
,: ci,. j i- c fl ir i n h. : r ne FF T i.: En 1 c i-r
- ari :i.:r. '.c u Tji cd in jetie -nin in- ch c- i. a'-.; t E 0 :Ce- *:*:.nD 3E E ; q..!ij'l i





u = *- F: i n r i




r..,e uiil'n ri.n r c e i:ra nli jc rj. i i r.r I .-r_,:ced .'i .i: a .; r irin c :'e


I. :.f an ir ir3 ~-n.:.,'. -.:-, dich che ;. ,':f an 31 i ail ,1-:e: if rth :e a3 e n: r

cluai C -: cal.Ti3lac ld : Che [a i i er r i e -nc.. nC c_ -ch ,. .

El-i aileai lir F i; a cern -ed tr cr j..-aie *.C r- nr .: b.:.r-,

-re in. .in :- ad ,iini; :cred dru i nhi-ch rc .-hc tic i r ul: 3 l .:n 3anrd ri

race ac .;hi:h hi :h cc r *Tnr i: .-iE .la1iii-i r JlE: jepen i .:r, i' ch.

r ere and ie nc; rel ei- .:.: r.r.CheI d-, irr. he j icie r: r n ain ch

"i :Pai ce ic i-re -r :nl' 3' .er r ifr~a-c rn *f t he jru-, pr Eencred

c.: "c' 2 i -r _-r-inc rcinal .-Tr i t a- h- 3[,. -_ce r.-rcA :li rc; jla ri.n intir. .

lhe -i:i'.-:il3bii I'F I. a dr UJ i ai j'l .t.Ej '.: a ra. c j jf ,c r3il








bic lo o .:oncr,-cratir 'r ,C o .'oLumre *:tf dis cri bu ioin che ib ,rp ic-.n

', I and lii njrcin i: c'.:n E.[- lnEs, anJ lhe- I D Ie P, eqJ3cicr .


,7 '.' I,"; r r. -*. c -_
Eq.



-.. l. ccrr measure fc Dica'.3311bS il t'" IF, in d ,-crmnirEd by .:, rrip rin2

che- 3r-:a LJnder chl- r.l' mi3a cure f er an .:.r l e ..UC I ..fih [he
p. .
ara rjnde r ctr: plasmi cur.'e ifcer the Inc r.3 --nouj5 .administra tior cit the

amte dJ' *.L'C.' ', uar. n j. Alcern3r. i' l.., if che sjame ac e i

Ajdmini cered b '. ,r:i and in rra"rnrcu? r:uct.as ne *:an d.*cei Tne bic-

3'..'i 1 l bii i[ F' Fc. t he r i r L i .:. f che tocal .1ru' e.-.;reced inciian ed in

the urine 3afr r che .-rj Jose f'U to: che r.,-.c l irug in hime urine

3ifcr inc r.5'.enrI u a d.ijr. i ni c r at ion iU I, e J.a n .


AULC
F E= L. 3





? .p.lb l
= 3 iE rA ,



Ei! triburcijn


for 3 -ompcoind cl :t re r t hait phariac logic ef fec di :ribucl *:n mus r

cccu'r intc. on:e o r more olumes or *:icmipar rent =c i:f th-e bId". The hichi:

pe-fused or cencrjl c.iopartmnE i- characceri.:eid bv. the her. liv'er,

anrd Liun s an e:.:chn.3r;e becuT r tr n ch-se cis-iue and che blie .d is .e r:., rap d.

The p'ri:. er u-,ed tiJ si-u i harac:.:ri .ed bt. -i muscle r, l3,id skin .and rh-.

ne olii b!L pc-rfused rroup LchJrj:c-ri.-r b c' h': '-ne,. c-Ech, hair, and

..:nneci c.-e ciE sue c*J.3impe ti peripheral jndJ d-c corFartrri.erlc,





-12-


re ;pectiv. ", in which chere is slow.: e:chane t.ec[.'een che s r.i j;u and

the blood 1 : ince che blood is the commnr.n carrier f:r *lisribuci:r.

and urinej is che m: :at :.Immorn mechod of e::.r ci:n of a *ru m-u'rirorig

cne blood cnrcencratcin and urinar e c-recion rjce : ch- dru" will alloij

,:ne co d*jra m.achemat i-al rel ac i.ns=i ; as; r3 t hei a : .'orp.tci'n. ji ctribution,

and elimination of a .:'mp:.und i:..

The pparcnr. *olur.;e .if ditscribuci.n I'.' .1 i a machiemac:ica ev:. re'..on

for erciimacin; cr ]*efirini hc.wj -:cens.i'.'ely ch-e dJru. i discriaoued

chroughoiu che btoa. The lipid -.Flubilic che jderei .of plaima pr.cein

bindinz. and rhe cardiac cucpur w' ii 3iffec c .he discribucion of che

druz i .".

The eparenc .'.mluime f I ntriburijr. n of a drug is co-v' urce.d fr'-r-,

a semi-logarithmic plc of the pla-c. c:ncEntracion i. '.ersue r.cie it,

after a ,no;. c Jose i,* D, dru. ia .admini ce red intrai.'r."ju l, Eq.ian n c o

.'here the inict al plasma concencracion : is e c:rap..i ated.
p



D = ,:-, ,'', Eq 5
D D E




Eli ina con


The eliminacaion race conicant .L,, can be calculac=d fr.-m =emi-

1 '- rit.hmic: ploct :of the placr.a *conc ncraccirn ."er;ues r e and fr:om che

urinar: e-:crec:ion race .'erjes riue d eerminiing :hA e slpe of lie

plocted line 'I.j and u;ina equaciot n i6 i The elimir nation race

cansianc has cth unic :f rec:iproca l a ie ii if.


k = IQ. I I-mi
U









ihe bi..l.egi-. l c-r elirdinr ciior half-life :',., i f drc i dJeri:ed

tr:,ri, a -gr -phi c Pl-c r af the loar3 th ', ,f the pl -M3 c.:ncen rration IC I

"erEus t r.i e 'L in whichh the slcpe ci cthe line mi is ijused. t calculate

a3 ir t cr Jer eli in atio n or .*isposit i.: rat :-., 3 arr : ,k equ.a tic r




,=. q--
'- L


The biolo.g'ic hal -1 if is tine as thie itime ic c31.e- for t he drug

*:.:n:e TLr i L 3 n rc. b reduceI b ocne-halt 1 '2 and i. usually referred ca

in rel i.-cn c: t. e s rum .:.r blt.:d,! :onr:er, raction.

Ur i-,ar/ r .-: ret icn i_ a major path ~a foor el irrinat i.n for man. d rugs

tn. their meTrcabolites. f thei dru i- c. otall, e:rced r nchanced, the

rern l lear-c:e ,CL .' of the dru. equal the rpla a -l e r nce i .L '1.
r p

r. _re are c as :,- .. : al:. rI at in, c:le aran,:e which i h :,1 .'aS the dcL.ae i D), he

total area under che plaszs c n.-en tract..n cur'.' ALC and che ,.cal

amount. e>.r.ced in the urine '. i I, .* quat icns ? and i' I .



CL F Eq. 3







r '- .Eq. 9



? ,-nal :cear-nce can alr .- be .:al,ultied ifr.om rhe slope of the 1:l.;rith., of

tne i rinar:.' e:::retaion race s,d.A i' "-eriSa3 he plas.r.a concrencr cir:n at

:ridpo ints of e.:;cretion inter'-als C .. I 5 equacior. 1 .
p 1id


d A
u = CL ': Eq. 10
d r. r p mid.




-1--



Tin iliiti rac, r. rae a c n: c jn Ir I C. Ch ..: .rec t, :n rjac-e *-*:nst nr

i r' I ,and th i i -cr.h lr -'- ', i -ci, 1l ji 1i- *: j. -jl jr. [ ;r..LI -

i .s- iri, pi, i'i :..:.: inr ,:i Lcs r ..,: ArichL r 'iC r.11 -r nc-

in c.: r l ur i-.r ;:..: rec i, r i n c e 3m i.:.unr in rri; urin an r- r-i r-


il [ ,: ,A .- J] rcss ri r :.. r- 1C i. L- r" c br. .:_ reti.:.n i r ,

pi.: rh .: C n.:e nc 3' .:.Lr .: .J ru'J2 ..-: retr.e p ir uj i -ir c r.ir, r-_-i r'J r i -

cie l -ir. -r :' e -n iaiplin p. ri- ; I Cqua i.'S 11 a nd 11 .

rei cc i- i .




i:,, ,I .-. I = i.:; .: : Eq 11




P.:. 1 1. .; .. _. in e I r;
: = a c E i. -









,_ i-Ta prc:r-uina. i-sp.-=. ll ait.1 mi-.. a,:r a :. I Ji ._d : ir_ 3-. 131.-:

3rl, I, b i l *irucJ. .ail.- l j r,- 5 u 2 :i-,3i ;..j'.' CrEil err.BEu';F ;- I.:.rm, j

t-i rapeurc c: i.r. aprCca r L n J r.: a 1L:.u i a, 1 t ln n. in L :

P'. ;il.: 1 ,' a3c the 'i-tcr T, r i i i m ,Ii.. ti : r.:..jp I .-,i F rlr.cl i I-: i ri rn.:in i-




- em.::rrc- n n, I.

The ,e r.-e st cr r r.i,:,r. pr.:,cc n :..:.u nd dri,: .' i : .:al.ijlu a

r nm L c.;cal s ,e r rum ., c r, I r a[. l I ani ch aF.'ac i' h -I e:-.Ii
C

fr-e uni :.nd uiinrE ab.ch1 : pabirci dr3t I I r in c ri i i i.


L .
[ = 1 - r4. 12
iL I








TWoi Compartment lodel


Stw 3 ico part cnE E.,:de l is dj ined as a ma hemacical relationr ship of

che kin-ci.:cy :- .j is ribucion t substc .an.:ce in c'e bod:, .5 '.i-n a c;i

.:o.-partmc nr model do. eiti, one miusL calculated a volumee of distribution

tf r L..; h :,:.cipirrtc.ent '' an '. ,, j ra first order r ce cornstc:n for che.

transfer of tihe 3ruj rom ch e :-ncrl compartment to tne peripheral

com. parrrment ': ., n frrom rr- peripheral :c.-,parcrr.nc to [h- central

*.ioparcmenrt '!:, and 3 lirst order elimination :on:tant b" all pr--

.c-e se r r.: r.nE -eo r.il comparr.ent i' o:.r !k l. assuming Chat elic ina-

tic'n onl' c: : Jrs through rhe c:ntril :oiTmpartcenc I rf.i5 tno :corrparc-

mernt :model in which eliminrat'in occ-:rs ornl/ Ir.-m the central corr.partment

is reprE e -red U: .nr f.:ll u 11-ne =ch--me.


12
Central P----- eriphe ra
C,.rmp irtment .mparrent

10 21

Elimir.c ion



In a c., c:..icmparcT. nc mod lc a smi-lco arichmic ploac f serum -or

piasma, c:orencrtici.n i' ) I.ersus tine 'it) ield [us scraighc lines Lv

l~a3t square; jnal isi. the disctribucio.n : phae I and the eiimination

i' phc se pha:s- The race c.nitaint of the first or distribution c.-m-

parrmErinc I' ; is .:al:culateJ from the slope im' o. a second -m-l o;-r ri[nmic

plot of the serum .oncentrat icn obtained by. the .me.chod of residuals.

equation li (5"'. The race c:onstanc for the second or elimination

compartment f is :alcul aed frcm che slcpa I'r cf the- least squir ar

line of t he semi-logarichmi: srum conc-nt ration .'ersis time grapih,

equa nicion 15 i' ).


-15-








= I I' - I


: = ,-'. I-. , Fq. I.



[The c r3 1 i-in: C::n:l- lnc -..-'i.j [tlei L bE Cal-'jI c3E .] 3' r.:.. e ,.. ; i.:. 1)s

rnr :.u._h _, Jher A and P 3ar r he *e-:c r apc i iE bILi.:dj i:C:lCi: nr._rC;EElC

cr. e r cri pfn a 3 r,, p in repe,:c i Trh r.: ,r. n i C i tI l :.. :

C.re. I r. j j .:.r I, L 'I 1- rh i ,: fC A 31.1 a.



-5 -: [ I -
F


-+i 1 + k + 1



S' l: 2 "'i



;. 1'



""' 1 l"' : '1: 21"


Eq. 1;







Fq. :i







Eq. ;1


'1 +


Eq. 1-


. = +













'LT EP TiALS Ji1D '.E T-i.:.S


Hich Pe rrfcrmnanc Liquid ,-h romaco riphic n a l;s-is of
iulfc'njnidj'i. b" t-i : Cijppre:islCn


lac r -r ls


T -n .niii .-rn :s3-ples of sulfanil.amide sulfrs3ua3rildine,* ui la.Tera-

:ine, -" ulfamerha rne, u tfap':riajire :ul ,1r i o- : '. .: .et lulit -

:-1 i ', and ju Ifac r.tnl -. 'let ..re is;sOi ,c in mi-chanrji. ani ripl

discill lei '.,ca r i )'.'j.'0.' t.3o I- :con. nc: rac i.:.nr ,:.f O i, ra d 2-. uC 'ml.

Tr-ci '. i :r. liccrers o.f ch -s standard slutLir.nr 'Firre inject ed .-nc.: r.he

:.ilumnr. ir. ndard sorlu tions i '15-' u.. nl) '..ere adds, d r.o 1.0 ml human plasma

sjmpies c:. ci'.e in 'i cr : plasm] c.,ncenc ratic . 100o l,. ard 25 u ml.

T irn ic r. pi ama saimpl- ;-ere ilncu'baced f.-r 30 minuces in 3 '-C :Jcer

bjcnr cepr.tceinar ced vich erchaini' 11: .1, centrihfu ed 2000 :I foir l'

,minur.te anrd J ul of the sup err. aCenc inae.:C d or 2- ul of che in icr .

pl.-isr campl- rs' inj1- red direC il oncE: the column, vi.r.h.:ut *: ac. pr.p-. r.ina-

c ion r : *.: rac i..n .

.An 'i.C FGPC l2i- l quid chrrn3co'raph '.'3 i equipped wich a :l'del

-.0 ulcr ji :-l c jtbs: rbrtce j.-c e .c .r .'2 rni .. d'u l pen re.c-.rder"*


"Forr D.-.dge L bc,.rjtorie:, Foirc D.-d,-;e. l zi.I0501.

Hifrima -L jF.cihe, lutle.', tiew ;erse.' ', I 1 0.

tBrdici: Jj)ck.sorn L .bora,.r- rie M'us
l t'-ier. A.ssciace 'ilf.-.rd jss achuss et I .

-Houscorn Inr.sttrunencrs, -.iscin, Te'as 7?.-53.


- 1 -








- S iuse3 c quianci ic ace zor.:cr ciE1 i i a fun.rc.r i.n .of pE r,''h e i rrriu.

"*. .or.1IP, i r -rs='-phas: *:-,ln"' .a u-eij l cn a JLc r. r.hch3.-o1

mobile bha-s 3nj .an in-lin- cuari *o iiu n" pai: d : ch .:-rail C H

mI MI le Cghai- ai eslch -r O,1 or I: ,'*. =r Char...1 T .i':.iJL' i--: rLo Ci,:-

o.H c-f .-5. or 'iLn : l-ac. butW f r ad- --: e cc aj u r. che pH cE ..i'0 aji

S n irmei b 3 pH ai.--- r-i- a i I : r. T r aci*. T r ai triplee j Si E J1-

ra l-il anal .i e, ere co- : d. ceJ .c r i. nc ce r.per .c- -e 1- C :1 c .el a

0.: mi min 1.:'' r re.




E:.tracci. n an.: arici n


he- recercr -:rn cir of s ui:'o.n3ri~ ifi : [can,1 r in so:lijr ., or':,.

nEri h.ano 'c3cer are cie.'n in Tabi:.le5 1 in_ 2. i j :.l rc:.r of he r. a

5':' Lha I>i srom' I- : 3 3an i in r- ic r ,Ll:'n rime o.:.:urr-- .'h-n ch-

CH .ias reJucea C -.1)11 b" che al.:ir. :.rn f 3cE tu ffE t r C: rc e T oi

:irlle. T e rcc nei.,tn cime of sulfaiIt ch3:inc irn rrens :-.dj il

L'e nci on r irre of ii i' t r zinEji [cr i u ji f ri ine iul fit .. o- le i-.nd c i-

sui;-',i:.:: ,i e I ': a; i-: rea' ed y ni ch mr c bi le phase ..sn: 50'V -ic r 50i

acr'-,an:._l T b le 1 .

.'h-.r h- r moebiI= [-ha1 -- l; .. r- c J ci..., "i-. -: a -_ r -li:. ci r- ,. 1 l

"- Che rc enr io.:n L Ti Ee "3, inr:r-35--J tor u'lfa uj ni i n-, l in raz in-.

.uiifamicT i ne. and .iuli a riJinre h rec r.cl.:ron ci.-es- f:-or ch.e remaining





luacir- .n.i, o:i, arue :1ilford.. ,la-sacz.-.usiaur. 01 .

Burjic.'-Ja:''-:on Lab,:.rac,:ories. :'!uA.ZlI-.:gorn. ALI b--e.

r-la.:1.il aceci: 3..:i3, Fisher Sci-.ncifi:. Orianl a-. Fl i.-ia 'SO?.

,rio:.n floJ.-i -.0'., lri.- n Pes; arcr,. ni: a.'mbriie--, 13s--. u-- cLLS i '-L sl .











T'ble 1. Ret rn 1.3-1 ci..e mi.ute s .: i f Mna-rides in :3 cer l chan .1
t 0 ".,' rn-,i il ,l phaiS .ich C.: ncai t r.uffer ,p.H -.0 0.' no na :ichcuL'
buffet r ,'pH '.w: 'i.




7H .00 pH .-.5





culr t nrit .at 3. .r "O






ful f i: rid i 5 .4. f

uJli fis.::-.a. :.16 ... .0 ?,. 1.

A.: cr.'l='J If ..:.-.'le i "., 00 2. 'o

"i i r hi a i:.:*-1e ' I .00











Tat -- ...eC ii[,n eri i-.;i .:- iu f:.n tle I ca a J.'ra r Ie c I -,,:-1.
0 -. h.:.l-ill pha e '.ilh ac- r .a[C .uff r pH -.. 'J a-.d ichr.:ut
t t fer ':H .i .









.uulf anil ja JI 3i 1
iul1 uaj nii ejin. 3..O'








'-i f 1i : : _i .. :'0

L, Ca.c l ulfi.:: :i :i" i. i .

,ulf aclhi i_ :',lc 3. :.. :l0








uIl -:nmi.dej 4ere reduced e..eap focr iu i;c::ai:' c which remained

:.:nicnr ,r .

irineni ne compares he resu-ilc presented in Table.- 1 and aei H

4.00. ic i: n -c .d the rece ci.:,n timE S of :i.-: o- f -A if'-r i.r ije-. .. ere incre a ieo

.ner t'he mobile pha s 50'. [ac r i01. -ie chanl :. ich .i-e .e rui f er .

Th-rc t;. no S: i-i ni io.:anc diff renice in che r renc-, .:.r, Eimei ofr" -'lianila ,ide

o*r i'jl fa an i -j ine in a nc.oii phase i :. 5' ;jaci r-'r 5'. met hanc1l 'six h or

'ich...c ch. buffer o.r if ch- mocil -ae pha e U..ai 'iswa r -.O': r:eCEhan l Illth

the buffer ipH -.001. Hl i.e'.er. at pH ".5. jse of the 60' .aicer 'J

ieChani:l! m:.bile phase result e-d in in inrr.eai:e in the recntncn crli, cf

-ijll a-'janidIne whilee reducLin.2 chat .:.f ; lian nil.a id- .

Huilma: p 1'Lua -iample 1-ecre p pikedJ .i h .E 'n arJ3d cOlu lti :.ns ,f .-. ii fona-

mide- and the ret-nclon rime recorded. uli'-nilanide and solfiraunidine

-re n.ot[ e c3r.able 'rom clndL',eni,'Ji erun pe -aks- in the '0: 'aer. .50.

r c.han-.:i pH .00 I m.: oiie phase 'TaTbie 3 '. Sul fi.o:-:.aZ :'le ,and ic:

7 ne abli ce. i, e a c .'isulfli:.y ..:.* -, r n.- c epa rabl e Cron erd.-i.: cno.j

:cn-.'.nd a pH Ionic u ri upF pr e:'i in did *jecirea : the r ,e ciio-n cime

tf :.i ulfap -rii ine and sulfiachiazole in pla!m: -hile Ch.a o.rf sul faiechazine

remained .:'nscanc i'Table 31.

'i ien che mobile phase uia chane..di C:. D wa'i r 40'. me.hanoli .Tab le

i U. i'lfanii iJde. s,-ilfauanidine, and sulfisoi:cazole and acet:"a'.!fiso:ua-

-:1i :;ere no: de .-:t e bls ac ph 7 5 The re.-jainin: four uilfon jajides

'ier- de ec L.abie wit h an increased recenc ion Eime .at pH ".-5.

B.' cc.mparinr, Tacle- 3 and -, the reItCiticIn cilMe or the det-ectabie

sui tf..naj.ide,. ':.s inc r i d o:y he 50 5j ii :.bile phase e ad. pH 0J and

Jdecreased ac pH 7. 5.












2ole 2. F w'nciE: n rir,- '"i. cJEaS ...A uln: i n'ri.an j a in sci.ed Niu an rpl ast
-ar.l.S In 3 .'.rer -.E13fian l 1 0. i 0 mro:b le phise -i E ac tCj -
b rtff; r pH -.0 'I and '.ith. cIE Lb'ui er i K .- i H.




p .'" pH .. -.



'i .TmtiLr'' 4m %i'




iulf rr: z i ne t .

.uli ran r -ia: e .. .

'E j 1r F '* l r i > 1I


Sulr is ': 2 : 1 :.' ij '.1',*

-.a.- 1c -u i n!-ic.::"a .:!e ,i.i . ;* ID

.: I f 3 hisz:U .: i 3. r"



WD = .l.:it Jetec::-ab.l du- *c o 3.:er u -uri .:-n-.i f CO lrIE: jitrh _:i,113r
-r -i lE i ,E.n ri mi,-, ;.










fable Facenricn rime minutes, crf ulfr:namides in spiked human pisma
samples ir a .3car mrch anl iO'. -0, noble i phi e i ich aceca e
buffer pH -*..0,' and ': r h.:iur buffer ipl -. 'i1.



p;. ..R pH 7.-5


Sul f nilamid. [IiD* :iD

Fu il.a,ruani ine ID* ;iD*

WI Lamerazine .. 0 5. 35

-ul f.ame chaz ine 3' 6. i

iil f pyridinrie ..0 5. .O

ul S .:':a .:le ,JD*

. c-: -ulfi.oya le iN; c 5.0 :JND*

Eulf h t la::ie 3. 5 3-


i -. ~iec dJecectcble due cEj erndc:enoju serum
recentiin ilres.


,:.:mpF :nenc ':i h : similar








The plaina iac n .r r ti.reaieJ :r. rer.-rin rei.:] r. :u, .6 A* ii ira: n

:aul m c :-L :hazine i dp. riL i n C l fimi .:\3 ?l and a- c 3C Slauli r :.a-:.:l

.i' I in r 5 50 .:bile [ha;- ar pH C 00 iT I'l-i i anr .' T re rec r.-

rc n lrm 4 ;ilt ar 3aj.7 i. -uz L3 3-ani-lirz F r-- 3n S 3 1'3 .;:.:46 rr g ner
r -1.: n 7- l ,T.r . L rifi if _- r l : l: C r.-,-, a i l i n ,; ,J .-i j l I ar .:l: ',; r.- n .,: r

inang-j tri rher 0 5i J c' bi-'l-_ phase AE LH -5. '1.. I-r, rrn:,:n ru .e

i sui l smi': r-' i e n .a ;.-lf r _ri.j ir I as inr.: re j i., r', :.i 3S-.3 r.a r

a3 :. 1 ...5 -;hll. Chac ft.:r i 1 ait-razine *a-cr= e l l.- 1 anr.J .

i'lch rc he r .J rcbil- phas-, h ce~ er n_ :i rl icE- ch urLa- i

recenEcl [. n [i -n' b Cr'-El pa3s r 13 tri: 3r. an pH -. 0 T.it.is a and -. p

h. e rc E1ncl.:n ire *-,L s.ilr p '' i.ri and r sl r ,ch i i' in: rea:-J

b:. ch- pli ns a Tri. Ir Til-i ji .

I'hen aeru ,m rhe E.i,: :, i 31 m ac :i.:jr .: r, jl 'na 3 l-. 3ar

ea;il epa-3ar-*i-: anc I c. --r |H :r .:. ,. m I, P i: i r i c ari ,. :ul nilam t

-nid .l i:uariiJin are :r ,Je r-e ill-_ :.rL pl3E i 'h -n r:-1 b.: i h1 -.

t: -"0 .'3 m I h rja,-. 3a pri r h pH :al .: -S C c, r li I '.

*.3.li ifra az,,aLc E in. 3a * fl 1 9 a1rf ;: i e .e 1e ac. nIe in;.

r^r :.n Piuprp s i--CrL ar pH 4 .'i, re;rdlea Cr rlcer I.:bil :c b. Trrh3

ri ., eri.:..ji i seru c ,: .-.jna d -'ih ah .-'rb a - n .an b p i ., ra3e, f r i

c 1 a t:nartide- b.: c'a n,:inr pH .:i r i.r rh3 *..I .cr CE p r.-. r. :.n

of pi3 m ar, 3rpl- '.[l r. r-han:.L Ji r:r .:h;r e r.he recent t i.:n ir e .:r anr.

. nrlide a c.,pared _- che iic in-en lj ion _-.r rIir -Ei. pla-.a


adiTmpl p -para tion .:t .im. i.iar irns c .~if:ncld- .3 i ', a3.:c: pl i ihei-J

it chr r cacr. i n ci !iffr red b- a: L;-ia 'I .1 i. LeS..

C-'r c 'r..c Li.:.n *' c',.ncenr. r icr .;r r'es t.', pl:Acr. r p-i ik h1 i nc .' ri;u

i'J. i'. nd i n- 1 3annd 1'. 2:',. : -, nd r J l i ri .:f c n .a rd sc l tion

of sulfonarn, ide- i n m re1: h3r.-.l, '.'; Fi ure 1 r. -i h 1 i de n.: aced ti:- .c

Ja dif er-r.ce rin fens i" r-'," Cc: rred a ; f cr : i n .t, i:'.r sI p r. ssi.:,n






































I 4 "' I ni.
CC


c, A





















Fi ure 1. S~~ndard cion-enr ration cur'.'es of sJulfanilazide 31a., sulfa-
,uan1dinle (b)., ulfamera:in= (i ) 3ulfarechazine tid' .
sul fap.ri dine ie) sulfi o:zxrZole (i't it." acet'-l sull' iso:i: az;l
(g), and sulfachiazole (h) in 3 Vs3eri'echanoi 150-'O50'I rbiile
phjs3e i.'ich Iaecl ce offer t plH -.00.




























,JO IJ







4- .
I'L.







-c a

















-ri 14n, -'z -:'I-c c,
-a II
I-


















25 a'n IP.5
.CrJ~JT T~~J : ~.'~;r4I, m


Fi~~jr~ ... standard :.nc~n~r3Li*.n ~ tiZ.rfi~I iJt3

I n ,Iah3cJ naJe.mhn) c.Lf cw1
ix '.1rh a j.:r..i -. 5








and polariat' of t.he mobile pi-ase. The imean tc an.:ar rro:r of pF '.. he~ hc

aE crh i cor-.-n rac in ia 0. 017.

in Fliur-" 1, the -sena i c of sulfaluan idiie i: at 25[ rn 1i-

_rae3Ler char. sul iniliT imide a i r. pH -.0 in a 50:5 mobile ph3se. If

[h- mobile phasse r.mn inm at FpH 7 ,Fi2ur- -I. r s l, en:iit.'i[c. is re-

er-cj. :..ich'i :aunilfn am.ije pe.a hie hc bein r3r,-atr n an ulfaguanidine.

Tbhr- is= also a .han-e in [hie licpe aof r.he :tch-r 6 iSulf.-nanid.: as che

pHt chap~na in che ') J50 mobile phase Fiteures I ndJ .

if the muibile phaie i- rj:-. '.acer. '. m derthnDi l. --iiiL '.iL:. i f he

3a = j ''; for ljf. larn ile and a ul faI i an Jirne 'b are tche t t iensi '.

. ia e icher pH I' Fiier- 3 and fctict i ln ofch rth i Tm inel 6 sulfi.-i-

a ari ='.'ries in Eenz-ic .'ic" i t 25- nn in the 6il,'- mobile phaF:-= .Jich the

pH cranrt The mt? iensicle'- MOcbile phase is 14 -C' it pH -1.0j as sh-L':n

b..' r.he rrca -r sri:.cj l pe t ;c ulf an mide I FizJre A.jditI'nal dilJ-

Li-n o f ir ar olj'i i,-,n ..f ut fu.:I'Rnalidj Ind LnCrf~3rc j ten.r1 it' -

Ltrinr s co : .01 i.. f. i abu. rbanc: units futll scale Oi n the ulcrr-

'io.l c .i re-ccr rec-jr.dc-i peak hc ihtLs equivallenE o [. .0 r' 2 mi f

sulfI.r.amide from a sin l-e 21 ul i njccirn '.jichuc cc rct nc r aion or

r'ec.on'i tL iuc i n o. th excr ac it i'ins. et, Fi-ure 1 to .t

The oi.pe of he uI 1 fi.-:, :01e i .:Lr'.'-2 '..3 f- he rsa.i[ c r to he 1)j. -4'

m.:o il.: phase re;ardle_.I of pH I ~1iure- 3 an.d E. c ,rapa ir, F L Jrie

I and '. one -bsi r-'es chat che liope :f Et he- suliametha3ine 'I' Lurv "3as

Lre a.:- for t.:i 3C., ,u mobile pha e at either pH iu or pH 7" ..

iul f-.uanidin_ I'b. Fi. Jr"5 1 nd i and suif apF.ri ine I Fizures 2 anJ

I cur .sc had the samae sl.o.pe ac pH -.00 and. pH ". r resFe r.i-el re-

.ar.le;s of he Fpjlarn." ci he mi obie prh3i.








































.. b

7


,:.,r.,-'--r JT 7i~r. r : -,F 11 : I r.I I E Ir -I


Sc~i.indar of ul~e~ie sulfixidlahd:in.3'1 SuIE3

Su Itapyriain.e, I cc1urs.:l.
inj f icni a hi1n 3 :3 re rt-*nThrth an-cI r,CI n Cb i1.
ph:-s ;,i~~ l o.:ecC lbif r 3c F h- '


I


I

































1 :


.r


~..
i
~',
r,
..... ---,
:Z~i;-k-j


i4C -








ArD
)---










IC' I~l')







Figur-L -- jccand1d cnJrencrjaijo curves of sulfauilamide (3:* -3jfa -
'2u3n I d 1 e i. . Su 1 fame ra.-i ne I :uf ame t aZ in, -.d~

0 1. and su aI h fa ih h) in a watEri'mechano.I eO,'- -)) mobi e
phase wli h an isca,:r I.c: pH .-.


-,-C-








'.ic rmir : c Cl: n Ci e Li i .ind hr:om ac j.raph l: Fro.:edJur'


F.ur iulf )n mii.de-s ,i : if r, erl:ip._. :,lfame.hazi-rne. :JuliFp:.ri in irwd

:,jlj 1hia:.01 ,i .i:.ouild c.ie car.ar .d r.:.m, i i..lj:r 3 rjacr i-'. t 50' :) .:.r

. '-.i.' .chnar..:.l Ler D .:bil ha;e ac .irch r ph. ,,lf ni i.J- a ,a iF.l -

;I3rnidinre '.'r.i .orl" s-eparj ahl. frr m plasma in. .3 ': a[ c r 50' -ecrni r3.:,l.

m.:.b lle p-.na.e wich.:.uC n.:ecacE bffer 'pH -.- I .du-e c.: ch ir i crE .:. d .a

:f ri.5 and 11.2?. re pe.ci-el : 1 :.i: .a:,le an a:ec -'l:ulf i ::..: : .:.i

,I ;'re i par., Eid ECh ilEner T-.b1711 e Ph e lo.rni* : up;F -r j: i: 31*.. L

ai l-r.E L- reduce he ,. *il pi hai pi cc. 0.').

er,.:.r .s .'lcj y che sa.',' co 11)..0 n .l :of u1f.:.fm'. d frcn ::. A-1

inj : 1ion:.n .: rspii:d plasma am le-; .c tichOuc c.:.n-ri.ncrac n .:r r.,:..ri r..J-

ci.or .:.f rt e e:-:r.ra:c. a" f.:.r iulfant- i d.- rJ r :,uitr3 u3 ti re r

rhe c .:.- r e- irc.i- in he- -iac mechan i l- ,hai -e 3ra :3- r. .A. '.':

:acer .1'. ,-.ch oj .:,I r'n a -eca I:,u rfer .:, ;.H -.'.") 1a re i,:,r. : lri E

:. cn ac s :,:



E.M: r- ime r, i-A ,


The crial :ir, i c : d o:f r ile human Ol,:l, ier com :- .- :.e-A iu.

..ei-hin: ; ,.' c -o kg. 1 fer. jai. a ;:-, appr. :i.are -" 2 ear- :.1 ei-.n Lac

20:. 1.0 i : arid female p1;= appr.::.-:imar. el' ;-r.:nch 1_.3, -. w i hin

2'.'' 1.0 .. The br.-an ..:,lurc,.eers : er adminin sc re 21.1 C s oI f .l-

[1E:.:az 1;.- in a irile c-e andl -ilo d aT.pi;z Ca e-: at O. 1. 2, .. r., arn.3

Sno.:.rs afcer ad minii:Er a r .:c.n. The 1:a' '.'ere 3dmir nincerea 10'0 ofr

ui fi_ :::.a:,.ol: :.2 ::..' i-: ric. ':" intra'.'en.u and oral r:,uc. e ir. -

repliza E f r e- Eac:h r-.uE. iE .0 .a' rr Er i M,.j :PE; .i w 0 :t 3 ad .-il --

cr -ci:.n. i e ci s 'erO al3 0 Amii nic a 10r- MiC Oif : u Fifi-. ::::aO:. :: :'f








bod.:d.'i:.eih b' incr a'enou and oral rouces ~:th a 21 day rest period

ber..ien administraticn-. Eilo: saMples Were ciken at 0.5. 1. .2. -. -*.5-,

A., ?. 12, K 32., -- 56. anc -2 hiouirs rEr invravsn.ou3 sain.T nist ra ion

and 0. 1. 2. ?, 10, 12, i "23. 32, 56, 76, and 9o hours ..f r

oral adminiacra io'n in aog and wine. .All animals were rm3int1 ne.a *-n a

comm rcll 1 iet i 'P riri io; rno .* c r E'-ine Fee.' c 'i : h ad libicum access

to .'ater. To- anii3ls .' re hlusedJ in met boili m c3 I -s and, the urine was

:cole. eid 35 z .: ldvIed and frozen 'i C'i .

A 12 c' solucioj n .:.f sulfisr :'.: c.le -jas prepar:o in our lab uic[h

lithium hydri'.. .e. The : lucir.nan .-re filcer-d and plc ce, in cserile

i0 ml a3mrule?.. Thi sEoluci iOin wa5 u -=d f.:r b.:.ch che oril and inc r ,enous

adminiscration .Af the drue.

TrI partitcion co,-fficientn )f sulfi s:o a :Jle and aceri cl u fizo:\.azole

from t ..3C r pH 5.0' ini 2-'n:ccan l after a one nour incuoati.in perl.)J

was '.,- i for slrtiio:.: o.le ana 0.53.5 for .acet.lSulfiSc::Z.le a; quanci-

tated fr.:.r cthe previ.i:us rhih perf-.ri3nce liquid chromrrcographic priced Jre

uJsing 60. '-3ac r. -0, mechanol 'ich acaec Ce buffer IpH .00,.I.






Blood sample~ were taken from che cephiic .*ein in dogs and huc.an

and .ia the anterior '. na c a. in F- nc. Humi.n samules were drain


'Ral :-. n Purina, Et. LC.iS 1'O.

ULniversity" of Florida 'uine- Unit, i['. pro-tein feea, '2. 'ello. corn.
-5' soy.bean sil neal. 31 salt3 -' 1 rin, calclum-phospho.ruis suppl-ment.

H.:ifma T n-L.,.che. itle.:: .J . 'Ii' 0.

''.hearor,, Sciencific ProduLcs,, Ocal3 FL 32070.

**E.tma.n-'oda., F..nche.rer, N.Y. 1-650.









.1.re.:[l' inrc.-j 7 .i 3cer le 31! !i.:.ne .:.- r.t e '.'.:uc lr ,,tr c.mbE, Tiii n1 il i-

licer arimples .'re ca'.ern b a scerlia e '"rir e i irr i Ii .u;ji. re.C l;- rr'n

chl Ic31g aan.: pi;i an r ;an erre I; cer.l .ili.i:;.e-.:n.. ar.e. '.'a-.aJC ia.e r

,-jbeI Th. aT I ; ..er r. r ,tJu-e i'1,. i. .: a z'rr il mir.ijr. r. i -

S::race ., cr..-r ce. ir..E u li hc. r fr -i.zr e r.J j afl :e ;i hirh )

minurJ ce. fot r r:cai a3rd *-*:.rju.:a e.: I ,lIJuLr.-.n .J3rA l il rtir ir 3ri. j3ibu, in.

The re ir in n.. erum .. fr:zer '': l r up t: 1- .3 i'.:.r l .' :

"free" C.ilf;h..:- .:'.le, jc C 1 -s llfis.:' .:.i-.. adr.J Cr.: i Ia.:L d

t r..:1 ulf iti :- : .le.

jrum ri i r.ub rn u err i 's anal : r :.cE l 3an.: c :.r, j r.3 ,j i,j ire.:c

m:r lu u r..nii.Jar- edJ t il ru1 in :n 1 a, on '. u. u :.m3 r ic C lr'i l al. ;r

T
1 I u in; r :irIu : I ial ;c andar j

Th *:.:nj'ij ar.:d ,ch.: iS. a -,: di i :a ii In :-t he ar ,j ien Fer t r I





.-.r u_: ace t I L uC.oin r p-i r r hi ben:er.Ji -:.niu. [rc r- r lj :.r.L.b.:rca e i ..i


H+

F .: .hr.r: .phr: re .:- rt n ac ': -r rir



.in.der Lici.; .-:r,,ir l :,,. r i-, f- is u :,,jr.. 1 :. t [ he :lJLu.-.Jr.:nii t. 3 k,1 1-

rujhin t .: i .: .a r e J an end .int rea:ci., ac -.'' n.Jd .0' rnn T- I

'n:.r l jclCe in humaL n; i- c .r, i.lerej c: te 'i.0l r .. ).3 rc : il.

The rc-.c l bitirijitin .-,u ni acai.c n i r i-e n.::.rju'.; e.J ain-: urrnjugace-d.J

fr :cr i.:.n : 1 3c .J r i .a rc r .: che '.'an icr, -r. 'i reacci.: n :t",, .






E.I. t L'uF' nr, [Inscru-_.e r, Pr.-.,uct: iiilmir 3ton. DTelawarc.

Dale 2 -' :=.i .ner .,can 'i-i.cp-; i -.i,' ,.-'rp., N i i3s.a i, FL.




-33-


TEal31 bilirubin p-licrchbn-ened-: on ua m C 'rijflu,-.rob,:riAe IP I


H+ j I-een 20
.ed *.hr:i:. .im.pore ar. 5.0 rLm


. sjur:ac ani Tjeen 2'I is u e.d c-, .i :.lubilize che Jrn.crn u at~ fee

rilirubin: whi:h alon; wich :he '.'icr .o:.lutle. lu.uro.nicated bilirubin

reaccai 'W'ih PI:E In in iaci. TediiUJm tO m, eai re an end p:pint reaCcijn ic

5-0 and r(0 nm. The normal cocal billrubbin o*:'ni:nc r ac ion in humans is

iess chan 1.5 mg 1d i- 1' in d:.-' che nrr-til le.'e is n.y- chan i0.

M l-. cc til.

lncerferen:es in ches -,c[h.:d ire due to hemiol.'_:d -isa les and 1 i:ht

dejradai:ion .of the 11irubi i. All anal ses jere .::.ndu.:red uichin U3

minucres of sampling on icrum which 'as, epc in a .:ol, dark en'.'iron.n enc.

erJum albumln. 5er' albumln iw'a anal':ed :n E.I. DuPon A.utomacic

'.'lini:al ,nal- er '., Thi method is an ajapcacion o the broma.cresol

.reen i E.iC-i .a binding ,merhod .:.tf REdJ:e-- I 31 which h ',u later modified

h K mas 16..

Alt iiirn plus ECG d:.e ae pH -. :.1 elds an albulnin-ECC c.:..Tiplex' '.hi.:h

elicl:s an ab.sortbiin; EpeccrjumT i 60c nit. Tne end pcinc re acri.n. ir

mTeasured ait iO)L and ii nim. rThe normal rance in humans is 3..1 Co. -.

min dl.

Incerference- are e: e.:c r d in i.:ceri and hemol:.zed samples. All

anil =s ..'ere conducted Ai hin 30 minul:t- oc : irne.





'Uni:on Carbide Cor: c.*r ie n. e.' I':r o io 'Yo-k.

E.I. DuPonc. Insctr cenc Frroducts. Uilming.'sn. [.elaiare.









.ur, :ij1 1.'::.a:.:1:. ree '' ujnbound 'unJi cL ab.:1 J 'ruj s l .a-

z.cI_ an. --srum :, ic 'i ,. "ilEi1 0 :a"- re iEE- :L rri r, d :- r C _r z i ,a i'

1 part f cr jm I i:th p3r.t : r r- ari.h 1 : .n Cri 'in i r Ci m i n ri-

* 2:.')0 : i .nr-J fii c rrn t~hc Iupernr cenr chrou- h .h > :. di-'p.: 3- '1

l I c .r- *' Li-- r- 3. .

T.-.ral rc jm _-,i =...-:3-'...I. ij.:1 h dr- 1.:.. e-I .- e r-rr.irnei. i- ajLnr

Sparr.s 'j r nrd 1i Fr rc i h: J r: :h:iri: :ij c i 3r1 F err r',jm n.il hi

in a, b.. il ,n I -i c r b ar h 1' 0- r 1 h.:u'. The ,,a r.pi : ;r- ii:'..J [

.:-. [c:' r .:; i r. i r J =r-i :r m rr. : .:- r r -1 f r r . Oi'' .. .1. Ti.nr--

ruiperir.n c n as' adjuicE r, :' -i ii H I H. r ,h r1 a l olumII ad3J.j u

c 1:. 1. J5 1 i- ch i.-ric-hinl ini f',l.ers.l ,ich )i p..._ : 1-i. 'lii- :-: lr.- r

L: LHI. I, :5- .

mr- r t .li.r.:liei rs iul i o.t ice- [ il r r l i-.jp ra.- r nr . r .:

-inr. J ic r ;er '.: 1 I '. Li hr.T r. C.: r-ph .uDipce-d iEIl, aI .I.:..j,: ..,i

':. c.L- an:e i te.: rc .r rh a i*- Ti, r c r . i'l6 irj .-cr. a .. -E:'.J ap -.

.:*:.l 1m1nr..' A H:u? -I rn-ru imOnE l tr rH,,:.rir r a u13d c.: rcr.:.:- r.i

p.al- h, i trs. peal' h-e l ht r rEf i E a ct_'r"r :.J .-,.r..:n -

ra -Ln irh S i a hi 1 b Lin. : ui '-. a l -. ai -r a .. [" a 1 'cindard. "ru

j-- ,p .- .- i i e.- p ir.h -.a_ nd a3 e .:.1ur i,:rn, .:.I I:i f, -..:.l-..a an .:. Cr -

sulit .c::az:.l ..-re ir e :cea and arJ3 rJ *:mr *f pe3 1 'ir,r f

ru c Suit ach hii :--1 i '3a .: : f cr r.e.J


lli ii p, r- r ra .3 EL I n. E .t- r tr ..

Eur-Jick JmaC:!.zcn Lab:h.ri.:.rei il.J e '" -- .

*mrcfl- :i Lm'e:3. InIlut rd. I-I 1jC -

Forr '.zie L ab:or. cr e rle; F r Lr -. I .:c-1- 5

'H-. im-an-LaF.-h '. ucle.- : . "' 1 .








1 morniD e phase of v0 triple distilled wacer wich i.5', :onr encr.race

a3-ecri 3a id '-.' m rechano:.* pH -..'j0O' 0 used ;.'ich a flo-w rate of i.5

mil 'ir.. I : *.acer and mechanoi woere filt red I JA'.FO- 'IOi 1 anid FHLiP6 ,-000 ,

d _asedd b Yonic acion and .-z.ing raincain.' i usin_ 3 Therni ol .rn

atirrer.t



Urinar. u ti : sa:: : liE


Free ani acec '.'i :J '.I Oi- .:3: Ie Were measured ty.' coolin: 23 ni

urn C- O < 'C in an ice bath: suiffri:cnt 6 h:.'drchloric acid ':as added

tr. redu, c t; rh pri tco 3.0'. .After 5 minucea. 15 ml :hlorctfrmo w'as added.

rhe ,oluciton r'ncio ed r:..' crne ice bach. and e'.cracetion as zom:Tplcte in

5 m inurteS t. s.'iirling cn ._iolucion .ronce per miinut The :hlor forr'" was

rco.".*y',j, e'.vap.orate under nicrogen and the cre idue rec:n. cituted ''i:h

mechan ..'* TOral sulfi i .*::a :zole ..da measured b, heaLin tc he 25 mil .:of

uri'e in a boiling .;ac r bar.h for I hcur and then e:tracr.e as prel-ous1,

uenti .one d.

The re:onSEiEicud excrcic 'uaE che injeC:ct2l OncFE the liquid

cnromracotrscn usin: Cr e preju'.'liU 1" JesribeJ LEchniue. Pea3k heiAnc ia

also ued :- d cEirnine rIhe urinar' concenctr ician wih -ulfir.hiazo!e

hbein use as the irnern al [ Cnd.ard. Chloroform i e::tcracts ere jtilize'd

to reo.-v Q' ,. f sulfiso:a.::le and 90. A a.ce ',l '.. ,-sulfisoxizole fr.:I



if,jrdi Jacks-.n La ..rat.o ries :-lu va'. on, MI -'9- 2

lillip.:.re Corporacionr, Eejdior !L-.

"cien irfi.: Products, ',cala, FL.

'7orc Dodge Laboratcuries, Fort uodge, Io.a 5001.









SorJ.:l ur ine .im:.1 5 hih' i h d L een in.'t. c d i .. C f r 1n n.-.:ur. L-;n:ene

re .-d 6-'- .:: .ulfi .:* :,le rnd -)-. o:f Ae Ir. I', '*- fi l -'.- : le i1.i

rtnri" re ,: i :e d 'r. z.: s-l-1 :.'-aQ l- i and *i-'. o ,:et I1 .E r:d :l i l.::.:

B:r. i re rEz J A 3 .rirt n s-r n mic -r .- rf-r.:.ried *:.n chin-l .'er chr.:- ;-

Ec r pr' pi r.- i .1) : d dEerr: ir iL T r. bCi. r. ne rr. tn Che acec.l

i mer. lt.l r. i e -i Al -p. c rt- ijc c.:.: -r anj 3 an3 al.:ed

Ehruh.: zh Crn HPLC pr,; .c.'e uL pre-"'- .u l: r.ercir ..ned r;. :lc-.: uc l-e 1a pe r jn .-

...f" .-ch r m i-t b.L: ce s ac 5- nr. -nd 1l n.r..




-n ; 1 D i c i



T' l. cO jdIJ 'I e a nd indi r, t. ir. ur-i n nd er'-[r a rt.uir .-n r-

a].j '*zed f r c Eit ci 1 d!- J fference o arr ard -, dni n h Ji'..'.

pr rS im cr. cli e ',rcea r e Ii.ra:n i3 '-.miucer n- nter. Linl"ersir ..r r F i.r1 1 .

"[ree" -ulfrt-i:: ..oi-e ft-er incr,. i", ,J rdmai'ncr. t ri.'t ,,n ',- 3n,!'e.: d

F r E -E I-pac -r r r.rdsi U-j r a I s d i c rac *. .
3_-- L r ':,- :-..'cFa r r. [7. r. -.,de u in : a '." '.T ,_-'i z. r': ,' _-.,. L7....- r r.hs,,i --

le : s square a n 3 1 s an, d lhe e -I' d .:-,I re i.J'i- 'i : u d [ ca l julaJr.

a ra -rea icn line .-.r ,,:cr. i : 'it i -' >. :.:.. 1 fr.r ,ril jn r, inr. r i.:-.

iJni ni .cr .lr anj f.-:r "free" _e i i's.:,' -...l- rc : e ,.;irrl ra ce.




Ir "ir.r F r l --.Ii P r, c:r- itn rEindi nf- :



In ttrc r..m-ari plasmi -1r.ple pLre inc:it-cd in j i r btrach i c

zC: r 1 n.:ur nirch 2- .0, '. i 1. i0n. and 3,1, r, .. .,TaL' .d L

sulfi:,-'--: le ~. -nJirdis in 1 parit mr- :jn,1 icrh ? p-,rtt d u:,ble-di cil;.'.,


-" u r.3ic.: -i c .c.:--,: n Labh .r r.- ::rie-, u ;I:..= -.:n. ITl l .









.;,ac r. Di-al.nsis. as 3- .:crndJu cd b Tm.mbrane d lzd Ti;5 "rich a mn.:11- ular

cJ;- ,E cutofi f i ite-r .:fr 50J'':i afc-r incf ib~ c I- '.0 ml .:. 5 spiked serum

:'i, h .0 r Oll f ph:.;ph cr bufft r, pH -.'-i. ih- dil'.' c .as oll;r

rid 3riali- d b' Eh- r..r.i. l-' dsscribh d lqquiJ .Ehr.:m3 rc.r phi,:

i r hoA. .

















































*DichEr Ag, CH S3'03, P.chkl ikc.n. i re rl ard

'Flher Gram F.- Bujfr?, pH 7.41. Fishr Sci. ic, Crlad. Fl r1rida
? ,' l .a






















Phiar--, .'" ,. riC c i r cle- o.f :ulfi u-.a :...l -



The pharimiaci l- n.r ic pr: l-l : :. -, uri isr :.-. :.:.le ..a_ ;ec- ri-i d fColl,1: .in;




j3.ni irn, .ri.Era la.r,. i hiJm7an The in rr en lCj t :I li": i ,:ur": r : i :: an j

i'- rr. r :.'t. r -E C. ,D < l i : r,7i I 3rn re Iuir-e. 3 c.,. -, 7.. r ---r [

n:'~e'l c5 re-r for i i r. :



Cirirl - P rl- h.:rl
orr, p,-" r c i vq_ r,.h, r EI
Ioi m per m nc -- -- :f iirrar. rrm rrf



















chl i l-. r. r C n Cl. 3_ ic h r
21





[.1 m Jlr.3 rd .,



trir_, .ri:.:,n -F rhe .liff2 reni'L i -., ljri,_ rl *fr r...-comparmrrenr ,,:.del










.h. re : i .. r.the c:,ncenr r~ar ,ion f rhe drug iPn t'-.- plai t r ram. r, \ 9 n1

E are crd.'ir.e j .:ir in r -rcr:epr' arid r:h indi" i ,3Jal r-re cflani %r an Li:r

rhe ...,p.arr.rrnc-, I'.1,. ",, an. .1c are alcujlaI:le frrm .:. and I. [-', r r.e

c..n-r.an : for.r .iscritr-jE'on 3-,d '-'ni, ac r :n, r --pe .: .- i'.'el'" .-' 1.








Adrj-ini t racion oi f Siulf i2 I:3:a: le co D.:;-


incra'.'enc? ajmnnistracic'n. .A lease square- linear regrets ion lin-

o.f tch "tree," unbound, non- c-iir.i 11ni:zc iulfini .jol in 6 j:' lFiiure 1 5

*a .:al.culated uSj.in, a O:LII program i57 The rear. e. rjpolaced ieriun

c:in.:encrjci.r atr. : r-, cine iA, i- che fir: c cr disctrinuClor *-omparEtmenc

.as i1 -2 I 3-..! u ,il ,'i 3 ran e if 16. N c 2n 5.3 j/'i and .-

mean ec..crapoliced level ja :erem cime (T i fo.ir the second .-r elimination

c.omparmrernt .as ..6 .3 ; 'mi able -.

The i;spoL.sic .:n rate fr.im cthe firsc .:r .di'cr ibjcEiin *-.'-ipar -.enc I'

ranged fro:nm i.i.1781 co 0.1'"52 hours '1 ich a mean o:f '0.1 2' .'1 0n hours

'hic:h "ield- a mean hM -li- 'e c, .hi A. . 1 .6i hours t.-r ulfit .:':a-












-I
W el in te fir-t [ .:o partcenc. Similar analysis of fr- sjlis'o?.ao:nle

in hS e.:-n.j or l imina iorn c.-mpjrcmenc yielded .er Ilow nean dis-

po3ici..n rjace (': i of i). 0''% .cC1- hour.- .:r a mean nalf-li ti c. I

1 2.12 hours (TatL e .

Thre mean rac[ o'f jdicribucton bec.uen the *:encrrl or discribucicn and

peripheral or eli-iinaf tin c:.c:mparment I k 1 2, .az 0."il-0 .0049 hours

I[able 'i whilee che n jen race otf jiistrburtion from Ch pe-ripheral to chh
-1
centrall c.nTiparcoenrc i1.:., iai 0.i'22- .'"-0 2 hours ri.able 5 Thii

indicaced chat free ;uiliso::.3zile returned from the p-ripheral co the

cenrraj c.riparirment ac a faster race chan it had b-en distributed from

the .canral :-. the peripheral compartmenc. C:l:ulacri'n of the mcan

2I kI2 racial reflec:r thsl. difference in discrib'ution between che tyo,

*:,mparrmencs. in these t d.ogs, the mean of the k L'kl rac o was 1 o3,

indicatingr that the drug is returning rapidl'.' fr.-m the jistribu.ion site

fo-'r 1aiminatic-n frr-o [the hbod:'.















































I -
'I

























IC, L" r



C''ii K' "
r~`'-n crIME r,:,. ,


























I -


.-
-.


-J












*1

1






















5~


: .


i




L:




r~ ~










I
~ F




''


I
C
i







L












n ii *rE;-n 3u~JniE A


-ulfit ::.-:a; l ec':cra ce J ir crhe urin .-'


T.:.cl IAm:iurt f
Sulfi :a ., ': :.
I rri I [.


-i E. tiCur3


2~u


in cr. -- nC:.u 7.




-, I


,I.. -3







,.31-

0 .. ..


r'.. 5,{5


2- hu r :


'-r, h1. ,,ir =


-.1..-.-


.1'


ial.:,lJ i -r.c r.r .:r J.:- e- .u,7 .:. u 1.: .: :ii .:e ion *:.f ,ur ne -- li -:ur :r[c:.m
one indi ii'iual.


C 4. O0 "




'9, -i,








Th- mean elimin~r.ion ra e 'i in r.ie dc's '.s C'. 1-6. .0-00

n,-r I Ta e SIc r i: I oc -, i. l ndi-ates r le rs f:crilon c.f ree

rjulf so:-' -,:.l in c ie po.lstdi~ri r ur b : phase i l-, .: h ia as.-jl labIe for

elimination. TIe me'n L, ra:i .-s 1.3 3. Indi.-cLin, th: t 13.i. of

the dr.jg in t he b:cd.; .'ijd e in the *entrai *.-.'mr ar.tment .nd a iilable

tf.:r eli iinac i.an.

The.r .- ujrie :rf e :en r ;.i .:c mpartE n. r r ancedJ f ro 9. 03 to1 1[ ..''

liter '.ith a re i, n c' lu.60 1 ....3 L able 5.'. The men .ol -e ,f rthe

.:.)n.i or ;eripl-erAl :r.r, rtc.enr. ; a 6.5~ 2. L iT bl1 5'. ndi.; ting

that free salfia.:' a:.le 1 mi orI e .i' J l: J r Jd i rituCe in the nentrjl richan in

.hb c iriFheral .:.:'m a i rt:cen .

In '2 i':a, 3 .d I'Tbl- -'3 nd 26, the fra-C .:-'n bh und -a less

rchn i'-. for cie firsc 3 hoa-irs fcer incr-raenou 3 administ rat.Ci.n bu had

rEj lieh -,'I [.to a .5 ur ter Jdminis-craci.-n. In tre .ot er .10,5,

cr ii- t'ra:c .in bound I f 1 r-an-2d1 from 3U0 c: 50', zhrou hou'h Lr the ri a period,

-"2 -..ur .

Ihe ire=n amiaiunt of uli *-.:zoie e~:,-reted in thre rine Table 6 was

j9. -''. cf Lhe d.~;-e within '2 hours after adrmin:atra .:n. .- the end .of

CIr'e tr al, 2 h.o-irs. -- .17" .f the dose wa i e::.:rae ed in the urine.

Oral ad1iinisrration. From i: lo-linear cere sac on equations or tha-

:eruin *.:ancntratio r .:t f re`r -ul fiiozl afte roral adminils r ration, che

-1
mean rice .-nstants aind iL.re '..1623 A .3i61 hours and 0.'29-, .0172
-1
i-i.:.'rs 'Table ) r.-pect -el.. The meaor half-life .:.rr sp.r.ding cr. the

fc. sc r disp.'itcion r ci C, i ''oia .3"' t .76 h,.-urs and chei mean elimina-

cion half-life c.rresp,:.niin r.o te alci'er *d:sp..siti- .n rate i t -, :

-. -, 26 .03 h-aur I'Table '









































































































- I




















I I


- ..7 *1

























I 5 S


r~. ;
3


-1
J


~1



'' '? ~


1








The pejk ~ s;rum *c.ncen c : -ri..i had .ic .ur red bL che rirst airplinr

peri.od, 1 ho.',r rTables i o 2o T1h15 rapid abs- rtr, ti.n i;a due to.: ch-

c:,r,pound being ;i'.en as a s lution. 1-,e peak ron.rencrami n ,:f fr-ee

su fi ..'-:.z Ie rj in fro., r,:, t o i 5.i')0 u2 ir.i I tables 1 r.-.to 61 and

Lh- maximum r. ocal sui fisc' ole raned fr:n 13 ." :o '29.22 . 71.

The *iegree f pFlajmi.5 pro'ccei n L inndin s 3 lcul ced t. L bte 1A) o -~O0

ir. doogs: in rh'e ftir t r hours ,iof r.ne trial ITablIe .2 d 'n I. The

fr a. tio, n foundn d '..a less 'han c.'" in the r nemainin.: do~': for che fi'rse 6

c.ur- after .'ral. admninist ratio.n. EeJc:Jecn i and-i hours. the fraccicn

c r. n J .' a -I) tc ')', tj. h.ad inc:re ed tc rE.. t 3') in all d .es =aft er .

hoejri and coiTncinjued a trhis l.:.'1el IunL1l the end o-f the rial.

The mean am-:'unr e:-cre.: d in rche uricr. of Lhe 6 ii- ; was '._'0" if

chr d'-e .a I ho..ur jnd J3n f t he *I-.J e ac i:rn en ci [he riall. 3 '

h:ur- i Ta .- r For Ir if the 6. do:.s ..creced j3. 't". .: cr- J:se in 2-

h.:.urs; while 2 dJ:- e:-:.: rc d 3.' 5 .' and 11.i)0i in ho-urs.



.drminiscra .in f 5!l i .--.azile co .-inr.


[, rra'.'enoui ad3 .ini r. a i.on. Th-e "fre'e." unb o.n r n-iFie .aboib iz jd

sulfitso.-:a:-i in p1i:s .a3s anrai.'; d 3s a cuo-Co-rip, rtrnentc modei 1'Fiiur-

',A b a iNLi: pro: ram ,5-i. S Ac -e t' i.me, T h re n e.-.. r sp,,l.ate5d s0ri.

..:.;n. lenr.traLi.n : .f nd 5 on the ,:.i-d na:e a:-. ; .a- 1i-5.0' --. .. uC mTi

and 0.1-3 ..'. u. mi Table Si. respecti.eiv.

The disp ic i.'n r L irm he ftirsc :corarrnment I ranged from

'.-.d c. t .58 ,- ho.rs ..ith a mean of .536 .- r .03 ho.: rs which is

c:quv.'ale-nt to a half-lif e it 1 .30 .0* rour? 'Table .' The

i.e ln dispossi i.on race 'ro.m the s5c.- -nd coap a r. r imer as :o insider ai .' l cng-r.

3 hour r h
0.0153 t .u--) hour- *r nalt-i-. tr. i ot 53.33t 13.63 haurs.




-. t,-


s a j





If








i -r .j, i a r. e m- izD a r






















1 -'





I .


I-


I '


I -


1 -


_-"


1 r


2









Thie .-ian j iscr1 tj i .:in7 c 3an b eciJer- chn .he *:ncal .:nd p.riphier31

. m par ~ n r c s c i. 3 r.*' .ini.,3i ae I' c'ji:e s ase s c e r.Euri fI cr

,-nmp:un: r-ri, rhc h er icher a1 co the celr ral c rr p ar menr. i The mneari
-i
VK I i .'2 'r tl r .hi. i rs k 'jc; u.01u .i .1-. -L h .4r -

, tzle 3'. h i i_ -_, prc ,:, r.r i e -.cen.eJc hDi f-life r Ji ; : 3.- :.'le

in tile r 3 I r, n C i '. I- r.- i [ i

ri ler cli .li:,5ril: l t n dli rer c ren.:- Ler.era che *:crr.p rtrene 'i h ce

tfr e -suli .:,:' :.'e re di -ncerin: cr he p eripheral :c:-ri.rcp err. t jr. -1.1. 1

re r.rnin t.' ihe c rtrji *.lri- art ent. _-.r clinic' ln n i fr..rJ r.hc: toE d"
-i
iThe el cinar 3i. n 1 race .' rai.- r irn .-.-r." : 0 i -.r hours .u icr

3 rresn f g. 1: t .a-i : hTrs TI ble 1 Th[ r cr c . 1 1
-il


*.hi n ind ci aed char. .ni" a er nall r .' n i .'. .: f ree ilf I .*: -

.,ie ,;. s sa i ,,eI c,:.: e e -ereced fr..,l r.h po ,..: r i ribuci .e pli .

The. mn an .'iur m f : li cri h r i..n n f: r cne : irsr ic .-mo.ir T.eE

STa i- ? '. 10'.- '? 3 .11 L. .' .:-*rne-i ial r i e .'c lun e r ch :c.-..i

c:..o, rt-erLt '.. 1' -, + .' L. Th irnd c c.dJ rhA. t [ ree s i .t i .'a-

-: I s.= -riuch -'--re .i l.' ji. L-ur ej. r o hr'uJh.:u' le ec rd c riT.. rr,e-,

chan in che first *o..: :pp r.renc.

The i.e ree *-if pljimi pr.t-;in :iri rin~ ir .i"-: I j:, a :l :n 1 i'l rar,'

fr-,--i i0I r.,. rI*'' chr.,uch:uJ r.c, r. u al p eri.d: I TI-L,-S t:.. .2' Fo,,jr [:

hr.he ar imals bunrd less rhanl ,' :- sul.i s. :'.;: i:.e during : the firer hourl-

,: ch- t ri l I T i lebis .:. '-' .

rihe rme "n a'ruurnc f s i1j :'i :''-a--le e:.'cr4c ed in :he u ri e 3 a per.ce: c

.f three j-:e iT3r! e a9 ;as. i.c.. free su fi s ::-: .: le -nd 1 0. ,1 a.'- c i-

l fi az :. ar :,e end :f h,. ur- E re- Eli of Che Cria, "- h,:, r.l

15.. cf th d J :e :;.3s ej...:re.r.cd a3 rre sui s:.- z,: and 1i .-. -:

eaCt Sul is.- .Z.t-- .











able 9. The meirn amonc.. of :ulfi ,:-.: l. A nd .:ecr. iui fi l'.:3a:ole f I
e..creleJ in :he urinre of 5- r a. a percenc;Pe of the d.ose.



of r.o: e E:-'.cretei

L' lfi-.:-: -:'lO e -.:e fl : .A zole


Inc r a'.'e rio

2- hour i .6 10. .

.5 h urs 1i.'.: 12.37

2 hours 13.2. I P 3




Oral

2- hours 15. 1 C -

-3 no:ur3 O17 12.3

'9A ni:.r E 1r 1 1 2. 7.



'The ,.rire from ,:,e aniTjal w -'a3 no:[ reco'rdev.










Ijtle 1'. lne i 1 .:I.: 1i l I f- if :f e C -l -ulfi :."3- le 1 r a
Srin ;l a :'" i3 f 3 Eult i=.:-;.x: .IC






*,DH r sl r i-


1 '.'.U r I r | ,. i i ,-itu r i


i ". '"- -- i .2.' I'. _2, ., _,.






115 1, c s -t> z -.3
3 1 .i t I, .1' 1i s






:, S1 0 1.31 2 J r 1- 3 . .


!ear. .'_: .33 31 0- i. t -' .'5




('t C. 2: .11,] n:,C -ciee m.C i .z -u l fl-f l ,:.':S:._,li :- r., -ic -, . .- 1 i ,' i,, at. ic.,i i .

[riI3uffi.:ir-.ic jr03 for l,:._-iir.a. r re:r,- -:i.n r'l:*.

ri=an 1t *l r a d t3 jjrJ : .'i C i.n .








ih *l a, n ,f -a:er.clsJlfi .::.:le I Tac.1_ 11). I jere calculaeo1.3

t,- i.2-lirear r E: re-si.:n. The c, rance.: fron-i '. I. "'l1 1 .?i h rs aith

a -ean t i .r -' .-' l'.cEur The much more .arijabl= .-ith rana
4
oz 5.50 t.:O rg.a,,. '-.Lrs ar.; 3 m.ean : 3 .f -* 2.11 3 .urs Three pi s ha3d

a less than 2 h.:.urs, 2 ha, d 3 r I 2c..'e n -'I and -.0 h.:-urs, and 1

had 2 t, ,* *. ''. ho.-urs I Ti-l.e 10.:. iA.el'r i1ul i .3: le reach d a

r3a.ijTmum l .el. 3 c. 'mi 'L bT le t, . 1 C 1 r.:. 2 h..urs

afce'r incer- .eno-i cniini ctracicn in all -i' IFiTl ure I.

O'ra3l adminijcra tIr. FromT l.';-li- ar re:re33icn r qu' ci r-.n i ch r

sera, i, c, lcerl-. rar ciic.nS l t f re: st lis .:.lf ,:a:. z-'l af[t r cral adm nini crac ion, che

-1
m.eafn di s ; ra Ii c ; :n rBce co rnEranc3 and '. -;er 0.i O r.-.i a

I.' -! .';:) h1our r.-pe :ti.'-ly I'l a'i 11 [he b 1iolo ical half-

1i -- .: t fr=e s 'lrf .:.xa:.:ile in the cer.cral .:.r *Jis rirlution cc'upartrmn.nt

S i ran: Cr.:r., 0. S t '.1 h.:.irs w. th i m n a r 1.'0 ) .1.4 h.urs.

The E an half-life in the c il irriatril-lr c upar-tr. tnc it i i..a lonz,'r.

-.. t 21.3- hours ;.ich a rriane- :.f 5.92 .:.- h,:..ir 'Tabl 11..

.-eruri .::,n.:,ntrrarc;.:.n .: free iulif 1i s :< a~ le r'a ch.-'d a peak b'. th

rir r. s amp in period." i h.'-,r I T-.]blt - 32'1 This ra itd a orptg i.'n

.. 2i dje rc. the .i:.4ao nd tei[ n g .l-n as s iu[ in -.e l n: m r e-

, f1 ,i 3 .iz:.le rmnced frorr 3 [c. iDOI') .. u. r, ir h 1f the pigs ha'--inr

les ch .an w'.'J i'iL 1 s Fl!i s-Ia:''l. 3 as m a: rnmuc s'r'am c:nnc nrj ti'n

iT aies "2. 2. and 31). Toctl sul is :c-.. oll aI taind a ma\imun of

i, c.c : c:u 20-J.70 M l WI t: hiji he sa'-,- 3 pis ba.in, cthe lc..st t3 c al

sul fiso-a.<3:Z le c ncencr t ,:,n i tables 3 and l i.

Acer.'lIul iso'.xa-c e reached 3 -ira::.im j, o 12 .11 to 20.I0 u. r.mI in 2

no hours in all r pigs 'Tables 2-* 5, The r-i -llfe o-f acet.'l-

a i_:' x;azt. r3anc-jd fromi 1. to -.33 '. urs fcr en-E c ntrral :r distribution








K


3

'c,





rI.I I**r
w r :e I11tR .z'e I~ f
































Ii















I -














'3;


JZ

r- r-


3: 2 .







r- - I -- r- -







- 3 r -

















rjJ37
3: 7 -, -7 1



















~I : .7


w:

7. -
3:~ a


h


r I


2: -,















j.7










0 C


















=12









z mparrm enc it ,i h a an f -'. + i :.2 n: r Table F:r
:.2

c-e p.ri.Fherajl *-.r ml ini jcLI :n .i:i p a r.inri ierit c E a1f i i re ra i-

fr:, -2.'. c.:. r'- ..:,r- -irn I -i ., an .:f 21. ,' t -. 1:.: r T 3tr.i 11 .

IThe t :.,:a-'=.i atil F- i :f ,r lf i -:, :az,:, a. :al.: u1 3C1 c eql JI aciln .

rr.:,in che jrea ,under che .,ur" i i I iatr r .:ral I tl 1- I aI nd inc rr"v,'-,i.

'T .able r,.,1 ni-; rr ti.n. The t. .: a jL' 1 1 Lt ran j fr m 1' c:.

-.,,.."' .* in _,.ine t ch a ..-- an 3:-. "-.. i -.'. i _T ble i

Lhe d jr- -- : pla .na p r.- n i n birnd I; 'r: in .': ranked Cr*:n. r.,:,

h r h:.ur. c"e Ir ial p r .:-.d i T iA. -r :. i I. Three .: f chl- an j l

L in-.,'J .l [-.. chlan L chr-:.u. h.:..r che c ri iL T :ble- j- and :1 i i hi' l--

rhi f r ; c i: n :ud i"_n ci th r i.in l : 2 3 1iin 31 3 in :r-- r han ni..l cChr:,uilrh.:.u[

the crial 3 i abL. - 1) and

:'-, e .::'reci.j .:, [ch-. d.: : a_ "frre .' lf-.:.-il,- inc e. ch

'jriin ai d 10. '- a a -'..t l-:..j i ,:'a l- i n rhe .lr ri h. r.j t: I C Ct r: a

after .:i-: l adnini .rarcl n .:,r chFhe ir i: IT le 'i1l. c" Ch- end ..i C r,- r a!,

', I-r: ., ch-. am ii u .:f t r ['e -. Ilfl .:':, 3:.1. ,r.- .J a I.- ..- f c l-

: -a:c.. armed t:. crl nr ..ir i'.'e. l o. . Ti. an.:.nc C ... r- -i 3

-:e i l l fi :':.A ,:l i-. 12.' -.:.C the d,.: ic Che --nj :.r lh.- r n al. ,?










F:.. i:in e .-'r andr'i ni tract .: i f n.u i[ ,::. a:o :, r i c l-

Jata -r- InaI .ed a- a ncl e '. r rie m3T dei iFt i-re The i lf-

lit: .t i ft ll,: in; :,ral a 'i ri i-t racti: r n rAn r.:.Ti c.: .. n.:.ur

!ah a T--in f ". -1 ,- .-.:i r- I I at.l 12- . ipla Ctc 31. r 2. repr rced

a i-:an h4. f-l fe -f : .2 h u .-.jr: af r crjl a 3 Jr nin crat n r.f


























-- EE -.LFi,>.r', LE

- A:iET ILL;ULFI:,O' ",OL


-...


*
' -.4


5-.-


I*- -


I1. 1 c


,I I I I I I
8 E 12 1. Z 24

Ti ME I rr.u, :-.1





Fieura 8. Zerum c'rncerntr.aiicns. ... "free" and acec-'JsulJs :i i .:'.zo' 'Fi
in hi 3rans.


. 'O C -








sul f, ..--:a. a -Ganc ri.r in" anJ '. 9 + ..' rh.,ur. atcer incra'.erenou

a iinixs rac :i.:n f crhe Jri, The mean eliminxir.ion -:.r.arca c i k i ;'3
-i
'7.0'1.: .+ 'l, hour? -1 Table i .

Th. t.ie : '.a1il biic: i fi '. .a cial.:-ijl3 from the oral area unJier cte

:'ur'e I able 12 and trhe ca: 3lc:j ace. ar- a under c e cl jr'. I 1.

rjll'I-jine inr ra-enoijs aJmini; crar ion a r. The T r:. a 1 a t. li ran J

_r.: .m 116.1 ro 6: "i, h a mean 16l: 9 2'.02' T L.ae 12.1. 3T

reason ft.r ec:::edin 1I00. c uld be due co 1 cncerc-hiepacl re:'.' lin r

r E e Comr[ i-pI.r:n *. diftf ren popular in n apln c 3e i in re-

rel d a3 ea- blm.va lair11 ,:, 1. .') 1 1 .0' :,i Lh r .r nie >: 9-.0 .

12 '1 0 .

The bc.ilc.i cal: h I~f-li fe I .of ;: ['.-l u!fi :.-.a :l e riarn J fr1.m

ilu.. [,:. Ir.. l r ,: ',ith j me.an :.l 1 I.' : .23i h.i, rs 'iTale l'i Ti[-e

.i-.;imr -eru, r ulle Zo j 7 Enc n ,ra rI n r an e' j t ro r c:.

'-.?- Ui ml anj reached r.an:imuim in all =ubjec -: hcr: :-or rer oral

admininri :rari.n o*: 2. )0 rin3 Is .' iultfiiS:.I- Tables1 e t' o ,

1he ma :ii r m "free" 3 n cocL l i: l fi i :..:a'ol. e 'i'-lrred te'fre r he

.irie 3sar 'linr period Jle rv che iru., seinz j si inis rce r 3. a -solucin n.

The :maz imum e rum Eree ,lfift 'a.:.Ie le- i rang d E r.: dI . '* to

1- .3E .mil Tab.les 2-. lU '..?' le rt tI, ma. imuT r..r41 sljf i u a.:.le

ra3icn~l fj -.1"' 23 5 ua, l. -:apla n .C at. Il' ref[-orrJ a ran,3

:f 1 "..- co: 210.6 us ml free sul f ..::z le f c roral adm rini S r a i n

Cr '.anr risin.

The frac:r.-n .:f sultl o.a:ole boundj cu o133ma F rotein? i s

Sles- than J2'. '" d jrinr che flr: e hour for all z' subje.:C a Ta,:oles 2, c:

,.). During hba remainder o, r.e triai peri.J. che 'as -5 t:,



-.Ca Lr i r. 3LC.L inzreJienL. l f i .:.:;a: le i. HLfifI:n-LaE.L3 heo c i ley1 ,











Table 12. Sin'l -.op.artm.ent pharmc.jkoin r ic ojarn-:ecrr_ in h humans
amtinliSerei a g.I nm oral d.je of sulfi0':3a.le.



;ub,] : [ d r_ .'l.T

-1
,'hou- r n I I' hi-.Iur I I' ,






10.' 9 -7. -3 2.
0_,. lii 5.. 7 :';39. 7 -1 6.0-

.S 'D'. ".'9- ._,- i ".5. 0 16- i0

'''. ".' 29 1 1 -' 1 5 i 59 "'

5 '-'. 0'9'l .'-0if 10- 3 1 7 9

6 O. C'. 8, 'i 1', i 3 :.6. 5 I rj .- ,.'



.le- n ,.. ,^ ', ".-1 1171i.7- 16 .99
'D' .C1l. .95 20- .. 9 29. '2


-92;a,:"3iii cb I. 15 cs ci ulaed. usin. che ,e3n ~,': from Kiaplan E-c i. Ii6'i
of a humans afcer incrj.venou' .3.miniiicr.acion o 2.0 grdIas o.r 'f ancriiin
i ul~r1 A .:,3a .:.1 i: AU'C = '05..

.leaMn t on c3n .3rdi del a '. cion.









h*l'ic. 1I .le s han chi- :'. rre i.i: 1:' reT*p,* id I I i IJ .F=1- 'l 1 r

.anr chair re:. re ::" t:c nd in -i ,.:i i 10i.




C.'Tpar2 .:n :f hel-i. Fharm :.'.:. ir -r : ,= '-l i -. .: :. n Do'' .
F, 'inrl 3nd .,i-j..in3


Th ie ,e n e :r. -wr.la c..j irum i :.ceni.: ncr i. : .: f = lf lti- .T,.:,: .,_ n, cr. I

rirs. .:.rmi arl crenc .- I I 5 1i.. -2 35. .- ml ir. .:dogs; 2-.h 1 -. .

u.- A i. -;:.ir. and repo.:r i s 1 9. -3 1 23.13 in hurarn 12i. i r rCh-

s o ..:.nd .:.:- ri r.raIE. tc e e:r.; pE c. j d r Ci *:.r.:.er c E i,:,r 2 '. 2.'

.* 9 u,. l ir. do,;. 0i.- .0?-' u;Z mi in a...iin, and rep.-.rted a. 15-'. '

3 u 1l in hl-r. an -20': ih- eanr c.:iil iri i31 l ;rj, .:..n. cac. :.n

,- = A .a 191. : ; l rin .:.l : :1 .J. mi in s- nE. and rE-

-por: d 2 '9.0Jj u2 rAi in kh m-.,= I li The L:,'rCi nd fr:r a iric al.1

F-rum .:r.-~in: iac'i, i.- re n..r i.;nific' ncl- Jifk rE-n I 12 in i cnlr.-

-npe:ie :;plar. c al1. 1 'I r-epo'rted .a cJ.:-comp. rcm:nr mr.:del in humaif; :

Crhe fir tr. :cmrc.. m-nc had a mean c of :'3. minuces or 0. 56 h:.r- .

the -.:..rd --.jlC parcl m nc had 3 iieaI j : r '9 -hours t.ia l 13; :ll.:.i'in

incra"e-Icu= -a inri crjacion. The in .1.-,: i.i ; i'- 0 i hr.-,,r rd 1

hours. in w-- ;ine ter inrrj'irn.. im nri cracr i.:.n. Th, :h.:r-. r : _,




The h.ja -life of Eulfis .: ::.e in chle .:.:ni ozrI rmp r.m nc i : .'

A .' mi,r= in do. ni 52. 33 -hours i-n si. r. Tibhl. 11'. ir her or

cr--a half li eF ;ere .:,-.r.pirAblE r.,, t hi -alue pre io.:ujsl: rEp.:rr.d in

humans i n. . 9 ho.ur Doi :, rI h.:rr rr .:.L r .hi [ri.al. n. f .-:r.

.::.iparr nenc 'a ob:i:erv.ed in the Ihymrrn s'ojeCtc .

ter or. l ajdrini racr.ion. ci- r ., -: .-1 hl ur in human -.3"

:iour- in d.:. and 1.5'1 h-:Jour ini 3.55 1 iTa.bl 131. i h.e r, i di a: a-a
1
















title 13. T i- :i. i .:31 h f-2 ife r of .ul is::-.:3:.:1 .


i r'L

-U. ,I


CI
IE F p p


i:r.r i en u

'-ral


' ilne




In rai en,












Ora i


1. 30


1 50


7 ..^ ,:


C.. 3;.


if' ~Hfl ~ rH


:ir-


'.I -,C*
0 .. 1









2-.-.n h>ur -..'0 hour in w.in nd repd r poireJ 5.5: bour ; in h'.u ani

ilc. arc r c,: i adiminis raci.n of julfis'c:;a.:.!* Thire rE n.-. differ.;i.

in the hAlf ir E of u fi .. z ol, C, r c, .. ,due c.:. rh. r,:.u[c ,:,

iad ini 3cF.-.a iCon in d:-. ; And : inr If rhe .r .-1 : ur- in huin -an

a[r- *:or al jminii: crr c i'n i- c.nijmrp d rc, cr c, r pl-rrcc. t.. I rljr,

r al i 20'. rher n.:. .J diffr-r n.,: in :h-i r.jur..C :t .3jadmiil iECr3cln or in

C e :.'iri .3r c rr.f cr IaFplr n 3c ,' Fpo culcja1 ch i r- i ,-C acjrriL T eren

m.:.oie in h1.m3ni Ju. cO C3a1ing l:.l:od anp .r cihirn c.he fiir C hour

.after inrc enous adTini 'crLccion .:.r -ulri:E,'- ole- *l-nrri nl ThI re

'-re Lare diff.ereir nc-E ne n Ep- 1 HIrr3 : h3J l T 'hi I ,n.: me I n-r

Sl -. I 4 ic r J i, i lor.-d b dJ:o -: . an hii r and E -n r, irei

1. i 1 .5' f' hour ITi':.1 l 1 i. I r. :. i'ond -ompjar ritm n .inle lad

rhe. l. sic i r c i c 5 .5. and 5..' h: ur:. ', it '-d rb che do.:

A . r:d 3.- h r r ii 1 .

'!.imum i':i .-'eCum 3:e: l. ulfi=.:. :r-l *c.:n:en ra ion Ta:.i 27 c: 2

'- -r lhi*h* r in hrumranii 1 o 5 .' u rd i than 1i 31 .ne 1 i .0 ca. 2...'.'

S. li '-': *er, -.. n 'z re 3 E c [ ar c a,-e '.1A E- 1 1jl : ,*:.z: at 3



-I.
Wa cer r jace : .n om [ '-..Lc r h: En rce i tne fo:.; w *lm- einu, 3O.:ec .7 i .ul rfi w j-

:., l ir. ine *2 Co hcur -= r'F- -.': arid c.. hr -.an E 1 Noj r ii, mT, 11ad

3 .3r, c ce i-.i 5 i ':' r iTa: e l af-ter orsl adrmin cr aci r hi h 1

longer ch- n che *.0' hour.'_ L- r u r E -.:rt-. e d J ? i2 ..irn. h d io a me.an

c, :f 2. h'our aft oer oral adminis: ra tcion and 1 ..r houri a er.

1nr C ."inoUj admin2_crra ;Cion o:f _Eulfizso :3:,.:e. ThE f:, 3: ec"-1-

sulfi., .,,:* :,!,e 's.3 .r ?..5 h uIsjL h s Ater ce ra3l 3.1-IniF. ral un andj 21.i'0 h',,r -





*arcri n a:ci"e inCrediien i fL = t ':aC .'.Ca l Ho'ffrfarn-LaW ': h. Ijr.le'.
N J .


-rH-




-61-


T:b e i-.. Th-e bl:l-:.,i al h lcf-lli e 'i ,
imet;L c,,l .:, -uli :t .-,:':aZ,:; le:


t r '.'eriu J.



S Ine rain






[ ri r" i -e -ii -







'-'r 3l
,, r, l


"I'D = :on i etctc t able 'lo I i i '.'u lfi s: azole .;as decactc d in dJi. .


ib*i3


I c I


1.S"


.'.33


31.0-


I -. .0


:~t' i;~c-l~11 fii::~-~:!~ ch~ :;









a tcer incr n:.u; ai.JminTi :- r .:.n .:f t l ; ..'.: :f-*le iz. Tjbl i -. ire.

'i:.r d J n:.c .rri.: bojb.i::; : t .3 e c lt f iac 1 : : ab l ice.

T.:e .i ri ic.ucl.n .:nc ca r.; :. ul' i ..:c:a: ,:l. I ~blie i3 r`r,: .ch


c .nc rjl Ec. c r p ir herAl c p3r r.rnr. . a 3re e: [ in h nm-im I0 .



-1-
h.: ur i, 1E' i. :" d -wt, ine 1 1.1.. 1: '4 h u r i, and rhI :.r. .z 1-

-:.'r T e di i ribuc r r r. cni- per i-h cral ..ripar rm enc c-r rch

.: ncral c:mpjrr .nr 1k', fa.j in um r.n l-.. ; i, .:. :




ion .: r 3 anc: 1'.. re rjrs in -.ir ''. I''2- hiur I :t1. i J
-1


tI. h'jran, '0. i?95 h ,rs *. ajnd rhEn ,:l .i ''..- l' u ur I', *r. r f.

che lr inrri ri.'.n *,: ,.:car .-: :hi s.- : t.h t, .f re

julri.:.': -., hlrr. : r ir :,uji-e crh n d,:. an.j n.:. e r in humTan;.

li .j if feren-.: in di: r ib i .-,n b.er : n chre r c;.:. .i.:.iT. rc enc= i k

a s h i he s r in lumi nin I i r. :. f. il :.',J b .Ji.- . r' ,nd c. rn .- 1. ,

0.? lal i.: jcin riijCr r CuI recEurnlJ tfr.,i ri -, peri-phl- er l : .; pa rc enr

ro: crh :e rrr l .::- p rc[r i lt t'c-_ i._ hnu in r" = :r' r'' .1 : in :in1

i Table !- Ti_-e ;iue .; r. .,n urr- en :r ! che m n rhji -iife .: f

;Il f .: a :aol- in rhe, r. d ..~.ri ,arr.ir-r.en .-c. r. c, ...i r : p.r:. J 1 r s -r

in ni'T n I n ', f'i l.:,... t .d j .-:; a n i-,r.e r. in -Jine Tatle 1 3 T

r cr i..' F I z3; repi:-cc a, ; .66 in human; '61, i. i' in a ni

0.': in ine 'T ble Ij n.. T-ii i rche 3i ,e -. rhe k I 1.' TIab ..

raio s o. r l : re ~Jt ie..:3: i_ o.aiil. 1ie fo:-r eii ifnarc n fri -, re p:, r_-

ji r r iit uri.e pla.: in h-jiumjns, .1 .--ed L':, *-:': -. rJ the le..r 1 aL .il

r in i n .

The m.ar. :. luim e ..[ ji c- rit-,jc iD f -r rh. c,- r l *.-'i ., rt i.cl. '.l .

r -: 3[pr:.:ilM jr.el c he 1 : i e in Jc.i O1 .r O L, j1 .'ir., 1'.- L '.bli 1 .'. I

Dh- a,-n '.-- ime jof che -E : n con art r. i r. rs 3 mu h r1 rce"r inu 'ir i,


-r, -















ci'fT!-,, cpz an 1 S r riicn ion r jnc af[Er inct cu rj3.s. a: lminIz.cra
c icn ..-. f S u i o: : 3 : r. I


I' u -1


Doir


rI! :an .: ) 1: m 1 d i.' l u j


;ap1 ar *l: 3 1 I -,r.


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1 our


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u 4Ii


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31:l Ic iTh-I r l-C : di c ri:j*ucl- .: n-.r.s nc: afr r i.rir.i rr ti., :n
-:. r lf i z .:. :. .





1.i 1 Iii




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i..76 iL. r ha n dn dcs n6.. L iTabil l The :alc.:'ul d '. frocm pre-

ous daca r 2' :.'. .67 L and -.5, L for '. in h',man [o. t i he

ania .'t ical pro,:ced.Jir.: n.i he length :if the r ri.:l I1'6. chi ', hciuld nc

t co i-parpcd. '.;lc r.he ,'., rep.-:rted In do-s and i..ince. Fr:o cLh c :aiculate e

i. for doi s. .s .ine. and hubran- cherc i]' an .ppro.-:im i e -'J'. difference e

in mce ani.l "I1 .er Che hum-.n '.olumr e :fi di ilur. Ion. The .*alure of

di crib.,.i c n in rne s:cnd c-.:u.parc. n i''.,l is Tiu h 1a-:r in s-.Line Cha

if d .? .

The rean bio*'.'. alabil c" i 'F I '.;j3 r aiccE in human 16. '9" ,hen

Che irea under C h incr. al'. cur'.'e fr : '.: .: lan ec al. i -. S. used

IT ab l l i Thi alu- i- rc. d r. h pre i-.ic.: da.a I 'I Chat F '.'a 1i2 .'-

in humI an rhe ':t-;. lute bluo ....1ilabill i rl of u! fit o-3:ile w-a; Z .- '. in

j.:I ard 33..:.', in .''re I Table 13'. The bio-i ai labiicii in d.;2 1is

.:loser ,to cb- ical 3ced F in 3r.,n.. m nd :.-.ine appe r cor be ..a3 cl

,di ffecen ro-r t.:,ch humnian ard d.-;; -Hc',e..er. th- hi her bioc.a l.ai l b i cy

in ihum]mn i3 duie cc encerchepac' *:.:i.r.ul 3; ic-n of sulfis: ii c:; le whl.h does

nec occur ir n Jdc i .and mTjire. The impaj ri :.. If u.,ulrfiso:.a .le is nor

-a orbced fr.- the ga5tc ro-irei iE in i cr .ic in .ine and is e:.:c re ed in

che fe-:e

The degree cr. procein binding: in -: -.- .aa i=eS chan 30'. in dJo:

F.:r che firsr. 3 hours and in pi;: fo :r che f ir;- ho r a fcer Inr.ra'.'nou'

ad-mirncr3ati:n anJd n all a. hrumns for the fire hour after oral adminia-

cracion c afulfi s o-i.az: o :.Iore chan .0'.I of suifiao:-:i ole a-n-j bound ti

plasma proceins in dc.-s 3a -4 hours after cral adminicrsacion of culiisoxa-

zjle. During che re-iainder of che trial. 30 c.o -'S. o lf sulfi.:::c' ole wat

b:,und t, plas'-i pr.-.r.eins in humans does, and swane .'hit:h compareded

far.'o rabl a.lth the 2'i pre-.'.u;l reperced i .. l Thi obs:erv-.atio:n















TnI ?. .r.lsr ~ *t ch 0'1'tl r'z tL I.5tr1. ..2t1.:.i jfli














h 3 a r I r1 t ci' i


St r- rr r z

f-I In1~ a- r.




-67-








Tia.l i I C.'mp risn of r. h i: i '._ail 1 il L." f ul fi .:S': a l in do s.
s.,ine., -nd rnumans.


c.le:. Ei.:.r ailjbili r.-



Dog 9 2-

I-. inre 9 .. -.

H u T a n ; 1 .. ')



'all: jl [. d from irea un-ier r.h plain r,a cure.









qu e c r :'-,at -n ini id*uj dIfif r.rce *c.urs a.-n- tich 3 a i'. an]

ne. ,armer. ir. f ren,.: Fift r.:. si::t -chr,. pF r.:. rnc oFr 'lii :-.3 : .

b.:.und Et.: nri-ar et r i r.r.ce in i in i:cro 'Table I r.-, o J ..:

-A 3U'i .: -i., onli" .,I. I, u lri ,,:,. -. ,L ':l a b:und li -' Lha r

n J r- *.:. c.c ir br i r.i i- a p3.:1C limited as Cne iserm r C:,nCer.-

Lrtc r,-. Irn,:L 3 e- 3b:c e u rJ. Thi '. I-. L he *C id plain]an cl-.e iLw

rjr i: n -':.rn1d i icih z.i o :L- r.,d duIrlnn chi: c r-p ricni.

Enr iTci t jr or. ,:. Fi-- r : ti c:: oi e' ::r-r.z r i t r.n i urin 3- 3 '*

Sth, i-,e 1 i n ur, .,af t r i rr. r3 -r,,.:u 3Jd-rlni c r r c ..r, jr.. ". 'r. :.m


che d..:.-.- i r -- h.iur ar c, r ,ra, l 3am.niir-:rx: ic n irn ; L', Tih- ai0ijLruni

S::: r-t j in cri urin i:, ir "'3 -" . the d;_,- jr,.j 2. :. r2. :..t ch

dJ c. in "-` h-ur-- ar -a L t u 31 n 3 J i n r. j3e'.i : 3 -iiPi-L r aL 'n ** t 3' ul J il ,"a-

:-l- rspe-tl -.l EE the r r in F r tri '.' j ,. h n:,r an h',ur- :r

c-he ir.nc i er,,.. ,i r .-. rou et r. e*._ .'i', rr r h r. r ? ,' i :, r hi

. ..,'.,." i: rr.e,. inr ;'.. ,- i T-a i- e l a i. i r. he ':' arr. r .-ra n 1 i -

Lr.atio I : t jbi Tn I m I t r inL r.a ;p a mini rr[l ri er I'1 z : t r cn

do ..a3 .*:r :, -1J in che urin b" CiS 3 apian -t 3 11i rep-..rted

thac .*' : t he do;*- i as ::r.ate1 J 3- f're -u ifi .:'-.r :.i, b" hlin n .

\.-: c. 'i .1 j s e: a:.- i. 3cco.: ir.ncE.l fo l S rchin r.jl ,31 che u* 'ril jr" -e ', iin

i n.n- .b h *' nich *:.. ri iL' r .e the p rj '' u- i r.ep rr.ei .'. r2-

.-:,.-re e.j a i h,- acer. meta:.:.m e r ij mair. Th. diU -er-rncr:, b--..'-

Ehe huim. ar, i .nd o and pie .::rLt'ion "- ls -luuld c- e:.pi ir.ed Dm'arc b"

ci- ani3"l iL '.31 r hcch...j u e.d. ijaplan L a. I1 -I ui 3 nrlerC, il .- i f iiChI...

frr aro.-f ai[, : m1 1n Eh1 b r Lcccn-L ar't- l l m eh 1 -l i I ni i -: .:; ir,-n:

u -jre er it..i': I :n : 1 n :-r boch r-E, ari d 3,c' E" Ui i 'c'.:3_ :c. .


- L. -



















Sit~i
I 4. 'I











_hilU. 03


"FreE& -erum
Cj,>nZPr3tic-ri of Sulfis;c:.:3ole















112.12


.)IJ.CJI,


Table 1,. Th,- ...' n - ruifi--o::azole Dound ;. !aa co human -erum




- 0-


F rer.w- eiiirubinr Con'':en:ir. tio:n.


[,:-' --ir Er'.e'n'yj .kj.,fDii c rac i:'n


The mean, c,:al] bilirubin once- ncrrac.in in rn .*i:,. adminic-, r-

i!lf:1.-::*** :01 I rr '.'enous] i -::hiLc it d sE a ic 1 : i3 1 ni f i.c r i c p .1'

lin=ar i r.:r3a e 'D i ac -.. I p .0:'. 6.. I 0 *p .0'i and

S .' I p .Oil h:irs ..ich ch= na':l rm e"el S at o 3 d : 11 ru 'E : r : r .

' che ner .c .Lamrplinr: period, hours. che rrmE3an cocal bilir lbin c n:-:'

cr'aci.. a had a.e ri ase c. '-'el hich .ire nrc : nif carcl differEnc

fra. m o:,.nIC r l al e ns unc i 5c h. .ur i in; D.ri j p .111

The mean :conj.S. acej bll rjbin i E'.--s alio Eno-E: r, EcaciEa :31r. : 1-'

Siagni -fieanc incra-i- at j.: rs I p '1'I ani concir.J-.J c-r.-.o h,. cM,.

f ampl in p-ri:od J p '. i, 2 ..*.rs. lThere : 3 i: nif ic: nL r p .01)

irim::lIuni r E n i'* nju:.3 d tI 1i r bin 31 12 o.r- l or:r :in: i.j.l i ch-

maTi,:i ..rr i m 3an cocal bilc lr bin c.: ncencrac*i n i L 'J- P ., ':iec* n 1Ln.:r aEe

Sa- o: '.d ic :. hrojurs p .1.1i ,rni h *:oin:ied -ith ch- :or.. in-

crea- i-n c:-ca tilir, itin iFi'.r, T1 .iCan in.dire.:c .li ,rjt.bin .:on-

cincr:acion i zurl i nec l nfitifi ancl diff.rrnc fr.or, che :.ncrrr

ior 01 l c c rou o I' l -, cI,. sa.plin. i. p;l-1:. .

The mean co al 1 cl r bin as s- nifi :iantl'i c r:. ac .-C '.icr meani

*onj:'j 4ted rbilirjuain I = i. -' p = .'j001' anrj "ic. mean in. re]'-e'c r t.1 .-

rubin wI. = ).3i1. p = ,*- afcer incr :ra-sno i i- racdm i- ni Th-

: cnifi:arc :c.rrel cior.n o:f cr ocai ad iJ :.n:'lij" u l 'E j b ilir, l. i: dUI c:o c r

con:rc...ixcarc in:icre3a in ii l.ej ronidj. acl.on a:[ i.'vic[ as cEcal c-il r u r:t.in 1

inc.re- .: if crt :Zl.:.jron. iJ ci.:.c-i an :.ci : C:CITa. i6 n'ot C:a3pac.: limice.,

crt po s_ ibilic of -i.rni:ecr, .j.- d e t an inc iri- in indirE.:c: billriubin,

ia minr.ri' i: iin nhe dW cE-r incra.-inoi' alinli c ra i-i 1- 3c-.






































S








S











S


S ..


I L I I





S17 ~.., -' l l
uc. .r r 0i r


1L 1













-7
.7.
34!








This eni :-m Te -.:,S'c. a:.: cj f.- ra inr. a n a r'edjced .:.r liTiced indirec- c :ili-

rubin .:-n.:,enLrjc ion and redu-ces r.he E. ic'. i f !is.pai :.. "pr.L c in-

bound" bilirubin or Inicrei- ad he-md dgr,;rad3a icn. -This i ;i7 further -Fpha-

si.ed he 51:nifi.:3jnc n- .iac r.- c'rrel3rl.:'n of **:*. n uij dj n.d indJir ,c:

billrubin i R = -0. .', p = .0' '. A.s cEh Le el of :i'njuJ aeJd iil ir bin

in: r-ea ed-, th,' indire: c bilirubin le''; l d e,:reajSed.

.i sec.ondr exY'larnr .:,n ":..ul, be chi c u'Jli-; .:.. a c' le alr.erf r. he fIn.cCi r

of che n.rr:-'ral h'pacc.:.:"r. c increase ci'j'j~a J la d billirbin re:ur.icar ion

inCc ch.- gener ral circular :.n in:eld o.:f biDreln" e::.:re-ced nrc che bile.

Th. r-.eult-irn z incre .se in cc-ci l t-bilirubin Lc"ull be rhe re'ult c f c -

increase l el .:.f re ar:icacE d, ..:.n ,j ated bil rul:bin alon: ,rich che

nri-rr l lee-. l f inijiri c b ilriJbin.



Log s--i.',ral .d]i ntstc r iion


iJhen s-ulfii o:. az l t ad.j iniscr; r, orall" c .Jo 's trh re r .a 3

si;rn ifi.:an linear increarjs in mean ct:. al I p .01', i:i:.jugate.d i' .1l'l ,

and -ndirecr I p .0 01'1 bilirubin 'Fizure 1i'il T a,:c l blll irbin r:ac',he'd

iL- fl.-:st ,ir fifi,.anc n pea ac 12 h.our ip C and a hi 1he r c n.:en-

cracio: n at -a hours it. .01' 'Fil.' re 1 'i1. The mei-,a c'i, al billrubin

l'.el ;e=,re siznificancl" increased 3L 'p .C' 10 I .01 arid 1

(p : .L01 h:.ur A .sec,. hr her p-eak :c.: rrueiJ -c 'o hours ip .01.' and

remiaine 2rea c r chan the 'c nr., l l. I'.-els ch r.h end of che sajmplin

peri.:, 9' hCur. I p J .OJ i Fiure 1 1') The me'n conjju:ted billiribin

le'.'el s re alsno lire3rl.r iincrea ed I p .1001 l i Jirin. t in, samrIll;

period. i;nifi,:nc incr. ases ,p .O I. :ere Coser'.'ed- ac i, ,. ird 1"

hours Fig ure lO'I, che Sa-e pe riodS in r whichh cocal bilirubin :..as





































































































9



--A


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9


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:r





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ilC


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LI


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f, '- ; ,; ijaI ij 3 -..1 -. rii. i .*,1' i 3 -, rji 3 4l


-


I I








si nlificanrl'- incireawei .frc r cho 1I h,:.our pF.rio.: choe mean :,.nr]il aci*

t-ilir-bin na3 rec[rr e, r,:. 1 l h-ich e-. r,.:c i ni ii.:ancl- i fferEnc

fr.ji .:.nrr.r:.l 1-"eil Th e rein C: .njui atc, t.ilirut in rEa-he. i:3 ma:.itTrr ,

,: r.c:z ncraci.n ': 1. II l J hut. ...urs. ; ile he P 3."imJ rC Eal i.ilirubin

I 11' :..-- c i red h:our: lac ac Ei L2 h.our sari.ci n, c. ri.:

I iiE -i i. he M an I ir..:ir ilirtjbin .as o-.c i if [ icancil' ifferenc.

fr..,. .: cont r.:. 1 l .* zl .Jncil clh r. and '9 h-. r p.: r .:-'in .01 ip 'lt n

injdir.C- bhiilrjfin r a- ch- d i a mei.--i .rj .:.f 'J.:. ,; i dl ic h:,uris hjr i a.

be'ji l co :* .J-ilini t c nd .:. :f rche trial. h,:--urt .

T.o all l.iirubin .r E cnifr icanrcl' o: rr-iat- .ich c.:rnju> ic te i l-

rut ir, F = .'I. p = '.I'.i1 and wich indirect[ .iiliru in F = .1.

p = ':001i- -hil *:...njuc-a 3 t.l rutbirn, a= il-:. r ,, ci al ,:,:.rr.i ed

.ich iindire tilut-r lin i :. = -'.11. p, .'001 I- e :i nifi a- ,c c:rrela-

ci:n *:o c'tal ani3 ;oniuju2.c ci. iirjoi in .-.:p ainerd h- r i t-i r eje in

Qlu j ro:.nidacio.n a- i n irea eJ Fe.d o-0 ] -riJdac :o :'.-, .r incr'. 3E'd ind i roc r

bilirubin .:ic urs or duC c. w r-- l ir I.tci..,n .f c.:-nji i acei d bi'llru'cin inc.:. che

ene-3ral ,:cir,, ti [ .:. Th- si. nificani r co, rrei cri n :of ir. dij r-. bi, l trutir,

.and cocai bi iru.,in illuicrac.d chea [the ilul.ur,:.lid3E:.Fn 3u:cci -i c.:ouJi

-..t c ,: n, r .:r .nju:3 i.;n ,: 11 hof all ili rju bin pr.o The n,-' Eci.'

c rreI 3 -.rn r r, .: il recr. and con ; juJ. aC- bili rubl in i : :i3 por..t i i

rh-ar [,co.*.i inu rec: t.i iruj in 1 .em ca- bt reducJ l. E [ .r-.'enr

kerni .ct -rui. if jiuc r.:.r.:r dari...n acc -i :l Ecan hr t ci l , 3la l.



C.in -'ari n ;.1 of i irutin L-' el i 1-, l z.


7h- mean cc.ral bilir,.bir r-e ch .j zia.-,iamu ac 12 o:.urs after inctra-

'.*en.,, ''0 9 m: .- i ana :ir l 10.31 m '.Jdi a.ninis.crEaci.:n of .: ifl .:. _:,








IFicure 11ii. W'ich a se .:nd increase ac :n hours atcer incra einouE JIrLinis-

crarion and hours a fr.er oral aimlni crarion. C::.njua;:e-. bilirubin .as

also. m :-.:imu.:n in the 10 and 12 h.ur pe.ri'd .. r :ral ,0.22 ma 'Jl) and

inrra.ernou.s (0.22 m ,dli a.m. in.i- t-aci.n of s.jlfi-s.jy:a:ule iFiare 121.

reSC p ccti'.e1:.. C rnjug'r at d bill rioi n as significance cle-'.ar.ed at ch

- 5 hour period aNd 'J hro h e trial pert. :d.j .Afci r incr'.:encui'

jaminiscracion: after o:.r l 3dr iniirjc3Ei'n. crn]jUi j -3ed. billruib n '.3-

-i1nif icncti. increa sed bewi'een 3 a.nd 12 hour- cni". indirect bilirubin

.a;3i t r 'c s ficanil.' i.ncre' .d after ir cra F .r.-'oi E admEi Iist ration but u.'as

sitnifict cl' increased at on .and 96 hc.rs aftir oral adJministracion

*.Figure 130 .

The coca!t tilirubi lr. irrrease, .atter cral :r incra-.eZ ic. s ; r.ini s ra-

c i:n :.A suitisoa.x' ol --a 3aF i acc ir p ni-d b:y an inc reas in .urrnidat ion

jaci-ir'. whichh increased che .:onjuLgcd, w tcer-a:.il.Ji le bilirubin lei ~.

This prel ern d C ...icicy b" redJu cing r the in.irie r bilirubin cleve arn

increasing the r.-E r-scluble'. .:>nju ted bilirubin which h i more easil'.

i..cr t J. The l'i.:ur.nidaci:.n a-c i t'.. ,' was r.dj.:ed during the la .:r

periods after oral ad.Jmini rat ion, allorin; cihe p..-centiall: tX::ic, in-

dir-cct iliru'bin co increase.

Th-rs '-wa a ne ac i. '-s correlac ion of conj.uatcd and indirc cit bilirubin

after incra .,rous IF. = -i0. 3 p = .0001C and oral 'P = -0'. 31. p = .003

adrinisrtr icrn of ,ulfiso:-X:az:l. .Afttr intra.enous administration,

conj]ui ated bilirubin le. .ls increased alone wicth an increase in cocai

Jli.rubin 'Figure 9,. Afc.r oral s, lisix:::ole adirnirL trat-ion. conjuiate-

hilirubin leK c increased initial', as cocal tilirubin l.,vel- increased

but lat-r decreased. allow''ina indirect biliirutin levels c[o increase.

This result leads one [:to ,:ncln.lde that some pachr-,logical e.'enct induced















































































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f i r: c. ) -. ; ll il i rji 3 ",r j,, :




- -9-


durinne oral aJminis riaic n of iu lf i iS :-.:zole buE noI,- atfEr inc raveno-us

admini3cra ii:.i .hich coJd ill:u indirect i:,lirutin t:., reach co::ic lieveis.

Th1- 3 pachoi o i.: al ce'.c c ci: ou.ild ce c:i:p 1 ined L:, che ph irmas 1-. i cal1

'tirs' -pa- :' e ri.c lj-. in, he "fi ri c-pa 3 ffetcc all ?1 f an abn ,rb.d

Jdr* i i- pres-enrej t[ cthe li'.'er Lefo.re dJis rit .it in :..here.a a after ircrs-

.'en-:-us ad.miLni cri c ic n oni' '1 .' o ,t r Ehe .:'iu piF a'e Chr:u i i che iit.er

I. ei-re-- b ir di .i i:. -rite:'j d ''r e:'..cre ej T. n thi c is rche 2irea[ c r *c oncen-

cratic n of sulf t :1:. 3Z.s le presented [r rh li-er, in iddiciCOn [.:. che i3:k

,of .:et iac; c.n o:tf te .:ru;. c jouilj te responS ibie b : ior altering i r.e

no,-rmiil dJe c:iflcci.:.n :f :.il irujbin :-o ch3[ *:ne :t; r'.*-e an incre asC i~n

indirect ili'jru-r n.

T:.-al and c.:.rijii-c.j bili rut in reichej higher le'.:els lchin co li

h.:uri .afer incr..'en.:.us admrini c rat icn rhan af eCr ral 7 a der inis raE i ion

Fiure. 1 1 and 1 n I ..f r or.til aimini~ tration. c:-nirj a ed j ilirut in

rtea-heA it.: ,:.:-:lum ;.i chin chil rCi-re period i1 1' h iou-rs b-jc coc.i3 and

iniire.r t. il irut in j di not rei 3.:h ma:.:inum ,n il "n 6 ho.urs. The increased

indirect bilirutin ie'.ei z h.:.uld b-e e:-:pE; re-d after incrravnous Jadinini-

craciEcn Ju-e o rhe increase s er-jm .:-:.tcencrci in of sulfi se-:-:o,,le ;.-'ien

.:oppatrc d ci levels f ollor ina oral admriniscr cion which h c'oul.: silo.r

suif isc'::o:,ile c,. jispl.:e ac re bilirubin from .ait'mrin. The inc-reasej

coci l and ir.dire,~. bilirijbin le.'eiv jt rrie end cf the oral addniniLcraci.:.n

cri-al -uppc.r : the h p.:.rhesis chac a ph r-r aciolo,,ical ev.,ent s Inju.:e. by

che .:-ral rcuce buc noc, cv che incrt: -encus roure .l-iich cauSej in incre3e

in tao al an-d in Jrec .: bilirubin, '. ch poss tile tcxc =ide -eff cc C ac a

tire mau:h lacer refer a sin-rle. oral dose cf sulliso:-.azole.

There '.ere no scace ii.:31 differences in 'erum cocal. c,:,nju fated or

in.direc:t bilirutin DoeticE n individual d:- after t .-ral or intra,.enous

aJdmini t=racion of c uifi.so:.::ole.















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-:i ne-- Incra.'enr.:us i .di Enisc rrac ion


.in analysis of "-riin:i usinf mean biliruoin .on,:cn ncrati:ns, re-

.:a. led no .: ; cat ict al difference iramong the r pii *:r during tine incerv.- ls

ifr serur tco al. L-.:njuaLCed o:.r indirect bilirJibln iafer intrav'.encu

admiris.ractin :f sulfiso;:: x.:le. The meran cocai c:onju.ae an indirect

bilirubin -.ere incrIadin; at th end :of cne rrial but iere noC seanifi-

cancly different Chan n:.n rol levels 'Figure l- ,.

Ti.al bilirubin :'as significan tly correlaced iich co;njuJ ced bili-

rubin ip = 1 p = .00'01, and with in..ire:t bilirur.in i. = 0.61,

p = .0"01i a' r.er incra r-nou administration .:.f ;ulfii o::. ole.



:ine--OCral Imrini sr ac :n


After :ral adminincraci.on f s.ulriso:;a::ie. rar. [oral bilirubin .as

5i:nifin2om :iv incr.-aed 'p .01, co 0.52 m dI r a :.urE I Fiure l

A p ralm el si;i:nifican[ 'p ". .01, increase .as also o3 bser.'ed in mean o.Ljn-

jug3ced bilirubin ac hv..,W r 0.3- mT 11 i'Fi0 ur 15' .1 significant

in .'j0011 linear decrease did occur over nmr trial period in conjuiarced

biliru; in Me'! n indirect oilirubin was nr.:c si nifi': nc1'. different from

control '.lues ac an'. time a rter oral sd-iniiscrarti n of iulfizi::.s ole.

P :..'e-r. indirc.,c bilirubin leI els did e'xceed ci:. njugar ed le.'el; after

the 3' hour sampling period: and remained e ,rn increased le'.'l throunL'ou

che rerrainder of the trial 'FiJiejr 15',.

7oc a bilirubin .as signif iicancl co-rrelated 'ich :con]ugaCted bilirubin

= O.5i p = .0001i' and ':ith indirec.: bilirubin 'F. = iL. 2. p = I.00il

after ,:ral adminiscracion Af 5ulfi. .ol:a l .









































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0
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c C - -

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C np. ris-:,n f eiliruhin Le'v..is in .-ini


ic jpF.ears chatc n incre-ase in c:c1 bil a irubin in the pi; 15

:,.-.: .-panied t.-.- an irnc :r-.as in .:.nju, ce.: and indire:t b'ii rdub n reg-.j li s

S:.rf h r c, rc e .:.t aLniniSctr.acrio'n. 3a shor,'.nT b" Lth p0.5si .'e r..C rrel.at on

fi.t;'::nc T hit~c hei r -r.1 "t ree" f1 ;i :3: .le C nIcn.;-nc rat ion

TIbles 27 cto 32 afrer incrae'.-n:Jus a.mirni cri acion Iii not sii;ni fi:c r.aciE

affcc b11urbin crncentraci:rs Fi,-jr 1E but orai aTini;tracu .:.n did

*;si nific iantly increase c.:.cjl p *. .0j,l and .?nj ugace I'p .000i1 bi1i-

-,:b in c c r. ,ours bur. .did n t j3ffec.z indirs.:, b;liruoin IFi ure 15..

rndi re.: biirrubin 3 clse:. l :orreice.J .ith .c.:.:nj u al.ted, bilirubin

arcer iunc r3'.-en,.J. admini r cstratcin IFi Jre 1-.I F but re:.:;ee.ed *mi:nju atedc

bilirubin afcer .ral adminisc rati.:.n Figure 15'', hn..:h su'g estts hat an

or-! S.se i n :3 njle1 d iifferen l, c han rne incr r .en.cus ne.

Incra',3 rnouJs a. drni 3strac n *o'f i sjl fis .:-;IAl, e co:.Jes not ap'niear cr,

afe. c r:li:rubin le' -el in the pi icter o.ral adJ. rinli racicn. an in-

I:rease in r.*:.c i billrubin c:.jil bte 3c:c-.npanidj by an in:_-.c a e ir. che

cnjiJu ace ,jd ie._ -.nich redu.l es he hazsri of indire-r bilirjbii r.:.::.i ','.

ih-iile ch;e ir.d re. t. il iruJbin levels .ere nc:t sizni fican l, i difrerenc by

es rher c r.jci enc, .ne rn:ild norte rnac LnrI ire: bilirubin le'.-;.s dJd

a:;.':eed ..:o-n]j- a d :1i r.t rjt n le-els .nly fo ,i o: in: or il a.jminisrtrat on

'i.ure i .1.. while e n., t.::.:ic le--.els of bilirubin h '.e be-:n escabl isned

in wirine, cher':- ;, a -i ;nifriianc increase in c.cai (Fi Jur.: 16' and

c'nju:ac.-1 (iF7ure 171 bilirubin i.n 6 h.-urs. a cter oral adninistraci,:n

'h.: ih ,idJ nt occur afr.er incra'.'encus iadrnisnisr cion. 1 his EuPg esi ts

chac an c.r l r d.J = .I ; sul fis .:a:'ole ra -'' c.ia've. a di j ferent effe: in '.'1 .j

than 3a .n cri"en,-u adDinistrar. i.-n e'evn t'i:.1ugr thce inr cra' cn us r,:uce






















































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