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Ibacnt itmtnanton of Jana TOXI3COMLOGY
re-143-2%C in Rats with Cholestyramine Treatment
aren 5, 1580
dntucont ste --_-- Gonductes bys
Saport by:
ries
Mixer saboratories, Inc. Sr Manasota $5101 Ssaoveeanrbye,r, 15158709 to 50 30 Gibson ant 30 Br Johnson
ForashD5RaGngiaoAnanB,rstesiot7o/n:8g0
XEQa Frise
Nrarasear, Dw rag Mr etabolism =
02913
2
Summary
rIentmeantlieonratosf
ccahrobloens-t1y4ramiinnelivaedrm,iniplsatsemrae,d
(4% and
w/w) in feed decreased the red blood cells and increased,
otrheFCe-l1i4m3i-n'g7gCi.on oGfroucpasrboofn-1f4iveviarajfgecewsereaftdeorsedivivdowsiitnhg FwCi-t9h5-e1jgCher FC-95- 'C
(mean dose, 3.4 mg/kg) or FC-143-' 'C (mean dose, 13.3 ma/kg). Groups of
cfhiovleesctoyngtarnoilner.atsTheweFreC-9d5o-s'gq'Csriamtislawrleyrebustacwreirfeicendotattre2a1teddayswitahnd the
FC-143-1C rats at 14 days post dose. The mean liver, plasma, and red
fbolroodchoclelelstycroanmciennter-attrieoantedasrawtelslwearsefceocamlparaendd tuorimneaarny ceoxnctrreotlionratofvaclaurebso.n-14
iFnorliFvCe-r95-(19.C4, ugm/ega)n, cphloalsemsatyr(a0m.i9neu-g/tmrle)a,tedandratredcabrlbooond-14celclosnce(n0t.3ratuig/ogn)s
6r.e0prefsoledn,t raesdpeeccrteiavseelyf;romfemcealanelciomnitnroaltiornat(7c5o.n9cenwtirtahtiocnhsoleofsty3r.a8,min7e.7, and
treatment) was increased 9.5 fold. For FC-143- C, mean cholestyramine-
utgr/emalt)e,d arnadt rceadrbobnl-o1o4d cceolnlcsent(r1a.t8ioungs/g)inrelpirveersen(t12.a1deucg/rge)a,seplfarsommame(a5n.1
(c4o3n.tr2o3lyictohncecnhtorlaetsitoynrsggionfe 2t,re3a,tmaenndt)2 wfaosld,inrcersepaseecdtiv9e.l8y;folfde.cal Foerlibmoitnhation
aFse-9a5-re2s9uCltanoafFteh-e14r3e-l1act,ivetlhye ehxitgehntraotfe uofrinfeacraylcaebloinm-i1n4atieolnimoifnatciaornb,on-14,
owfascalrobwoern-1i4n c(huorlineestyprlausninfee-ctesr)eatweads hraitgsh.er iTnhetheextecnhtoloefstytrotaanlinee-ltirmeiantaetdion
rlaotwse.ringSiangceentc,hotlheessteyrarmeisnueltsisinapprratosvedsupfpoorrtusetheinchounmcaenpst
as of
a cholesterol testing
cholestyramine in humans to promote excretion of FC-95 and FC-143.
Introduction
bChlooloedstlyervaenlis,ne,is aann agaeninotn apepxcrhoavnegde froresiunsewhinichhumhaasnsbeteon loawdemrinicshtoleersetderol orally to promote fecal excretion of the pesticide chlordecone (Kepone) sinaltrsatsand(1)exiasntd maasnan(i2o).ns aStinpcehysbiootlhogFiCc-95pH,andtheFyC-1w4o3uldarebepeerxpfelcutoerdinattoed Tcohmepsleextwowitehxpecrhiomleensttsyraimninrea.ts wNeorne-idoensiicgnbeidnditongascsoeuslsd tahlesoefbfeecitnvooflved. cafhtoelrestiyvradnoisniengtrwietahtneFnCt-9o5n-,1q7aCrb(oFnC--1P4peerliimmeinntati8)on anadndwittihssuFeC-r1e4t3e-p'gCion (Fc-Bxperiment 9).
02914
" ethos
MRaUdiSolaBbeSleSd IreR-1L43T-1S4c
-c-- orm, reas
*penotes postion of carbon-14
hTNhueembecsrpaerch45io9fn)i-c1418sclRa0bi.ev5l1ityAiCsoif/amtgt.htihse DclooavtrabioovfneyFloOfcaISrpboeocTpiifseitco(naRcisk(iesvreistTysa,obvoocvpheee.msitIcnravulecnttcuohrraeyr)ac rCeeriRzatisong,oa,rrsaditoocmhaemitcaallpeuritfyorhmaveevbsebenotnrepporruttieeds.separevels (3;
mselssarms Radiolabeled rc-95-14c
Cedo., :
penotes postion of carbon-14
ah(bReoivkeecrarsbtToraonut-co1tp4uer.el)aI.bnevlenTthieosrySatpneuctmhiebfeirccara4b4c3oe)niui1s5t.yt0o1oof4f6tmhouiCs1t/hmelgo:tsuloffDuertFaoai-tl3so6mof(iscesepecific pSacetpiiovriteteyd, secphaarniacsaellyc(h4a17ratchteeFreioozia-t1aiincodnwasT.acfiooucndhensiuoiaelabipeuriftory mneatvaebobreieonm
sninats
Fe-9s-t4c {FC-Experiment 8)
oTi90fen.nt"oimvaaFeolrectoonC34thrbaeohrloluetrsrSseraoRtpuierpvideoorrfwiCttFhoDivdercoahsto(islwn,egis,ttsywerteahlmev3ie0n4reawtetsoe(kmsw3ie0droheled,co3mnw3e3deiwrtnseioo3rn2a4e0n2ddo5G)m8a,lyamnneddaairnvaviidg3dere9daolw CSTritolatoleusecsmyertfaarnebieonleis)scmeoavcnsagewtsoateaPrnuariimnfmaeegDdiieaasrtoevulinytdhsCthfeoreewrn (dssoetsrhiansgso:rtoviiwnaoveort.addheed rats were SBorhiarnieestaRhivecrrowb,reRsatlisntgonLaPbuorrianteoriCeosm,panWyi,iniSnegtoonv,isM:assiacohsuosereit.ts.
02915
--.-
re-1a3-Mc (rc-mperinent 9)
.
.
TienntomaalceonCtharrollesgroRuipveorf fCiDverat(sw,igthwtelv3e00wteoeks34o1ldg,, mweearne r3a1n3do9)mlyanddivaidgerdow
of five to be treated vith 5). For 24 hours prior to
cdohsoilnegs,tyrtahmeinreats(wewiegrhet co3n00dittoion3e44d
tg,o
mienadnivi3d1u7al
mveetraelamleltoawbeodlifsrmeecaagcecsessantdofaPsutreidnagitGhroufnrdeeChaocwces(sWittho woratewri.thouTtheadrdaetds
Cholestyzanine) and water immediately after dosing.
Dosing
re9s-2%c (re-experinent 8)
Each rat was weighed, anesthetized lightly with djgthyl ether, and then RGLiveonf aa0.s9i%nglNeaClivsodlousteio(nviacotnatialinvienign)1.o1f3 mFgC-F3C5--18.5C-,1,%C/T2h.e0dmo1s.e veTshe 2.0 tahveeraagveeradgoesedoasdeminfiorstecornetdrotlheracthsolweasstyr3a.n5innge/-ktgr.eatgehderadtossewavsas 3d.4elnigv/ekrgedand wGiatughea1/32."0 ncceeddlies.posaTbhleedpolsaisntgicsolsuytriionng.eva(sMopnroejepcatr'eSd)byfiatdteddingwi=th15a0 2n6g of mFeCc-h9a5n-i1c1aCltosha0k.e9r%, NaanCld,cesnhtarkiifnuggifnogr.oneTehousrupeartnmaotdanetratweas srpeeemdoveidn aand used dfeotrerdmoisniendg bsyoludtiiroenc.t coTuhenticnagrbo(ns-e1e4Apcpoenntdeinxt o1f).the dosing solution was
restate (c-mxperinent 9) gBiavchenraatsiwnagsleweiicvheddo,sean(evsitahettaiilzevdei1ni)ghotlfy FwCi-tLh4d3iCe.thyTlye etdhoesre, waasnd 2.t0hemn1 oafveraag0e.9d%osNeaCladmsionliustitoenredconthteaincihnogles4t:y21ranmigneo-ftrFeCa-t1e4d3-r'aCt/s2.v0as ml1.3.3 Tnheg/kg waintdhthae3a.0vercacgedidsopsoesabfloer pcloansttriocl sryartsingweas(1M3o.no5jneac/tkg<). fiTtheteddowseithvas delivered mag2o6fgaFuCg-e1431/-71;4Cneinedl0e..9% NTaeCl.dosihneg csoalrubtoino-nlwacsontpernetpaorfedthbey ddoissisnoglving 225 solution vas determined by direct counting (see Appendix 2).
ELrcunrairntaes LRabiveChrows,reRsadlisntgonmaPbuorriantaoriCeosm,panMyl,miSntg.toLno,uisM,asMsiascshouusreit.ts.
sherwood Medical Industries, Inc., Deland, Florida 32720.
02916
in chotestyzumine mrestment Eicrhteohplaerasetdr.yirnafaomriGnreeoa?uchn(decraCithaadvs.oandthAagtwreoicugnohdnesdurmeppseoiinrotni7o-no62u0o)fdvibahese micinhdxoielvdeistd#y8uzRiabiayyinwmeeoimgfihesteadrevda:s RrFeeaccnehiivodetodvetohenolfyccthhroelaaetsetldyzaeamfimeniesedn.etdtruferyofaitntetgdhethTeuFtCssLoov1SrnLgIeCmootLfhrontPtheae-dpsereraaicdhineeswn.atzsM.2eS00sacn.rd5ua3l1g C(r50o)atooa/vaT/uasnay.vasT3e00ac.t3ual(5m0)ean9/dvoasreanyo:f chorestycamine for the Fertarelic sept cottection
Fe=0s-14c {FC-Experiment 8)
UtUrhEieSn'eteGniaentzdhaytfhaecefesotrhewre2s1redbaclyoosol:dlecwatAseedG21artadnaiynstEecoprnovsatlsshedo(vaseee:eiceTthnaebaliefnsagtas3oraweneadr.es5n)nd.efvoiirmhmaeersdicishaetseolfy cECourTgalanetsicfovener:dedashteothesAawthsheoplavereriaenirzsoaemcd:eiuibeec.d bPyhaesxessanvgiusinParceipoanr,edthparomTpitrley wBYscentri:
re-143-"%c (FC-Experiment 9)
oiUFrcihnteheasaenteednnyf1Teaceretashofvsoe,rreb16lcooolfdlayeevc.atsedMMeaatu1n4intfdearyrosvmaltpshaest(dsedeossvceeTrnadbitlhneegs as4etrssiaadsea6)tneafiosrmnmeeesdxtcinhaatteilzyed CCEoroTaalmuetsictoeenar:drenasTtetohecAatwhsheoPlvAeeFrLeeTIrZsaoandc:riSufbiacsed bPyiaevexasanvgiusinparteipoanr,esanparomLpitvelry vbaYscentri Semple anaiyats for caboreis RiFnoeamcoesgse1nainsudiontwighnoglveasaLsdieovcneperleiwneorfeVarpthirenegphaorPmerodesdefneoarrtae.cabyxibnoatnes-t1icenogmbaennsiatnleiyosnipsarceobsynehroglfn.owgaetnetrsing c$(o70n672e01 acno"tdmobouansdetdiionpngart1co.no0ef9sboiifnoltoahsueipcLshiscoammroaegveeonrnaitsael:fopne-TdlheeaBidhoioonosggecPneealitlsesnssevewrbeeyremtveaeaclsiuonrngeeddthe Trea combustion cones by veioher
ESreCsoacmdkearrssaonGnTrsnoosvntee,RmeesineitscneCeoh.t,C:enItneer., B22r0anWsvairlrleen,vilIlnediaRnosad,47721. 02917
-&-
cFoooxmnibodugiseznteairtn.egssuRainetdcaobvrleeedrybbollfaonokdcachreoblmolonsg-1e4nwaetrfeersomco(bmfibeoculesostgeidacnadwlitlhisvaemarp)lPeassckpaiwrkadesddMwoeidtteehlrmid3ni0el6dutiboyns
oefxpetrhiemeanptparloprsiaamtpeledosestisn.g for recovery vas made for
seioAtLlLhuetrimoenaFnC-a9tr5e-ctpheyeCrbioeergsinFnvCie-nr1ge4,3->m19i'd%C;dlseat,mhupsla,ensd.noencdGooroodfrectth,ieon
ra(n5e)dcoawvneedrreyFcCfo-ru1onm4t3ec-dg1g7bCauisr(et6ci)t.olny;aUrndiaunlepylsiicscoaltlheeacst1ip.orn0esvmiowueasrlleiyqusobatemsepnloefdrepbeoearfctoherjdesamffporlreeeFzCwie-nr9ge5-14c
paIpitpprehoatsptreidpartedeviiroefuocrstllyyFbCei-en9tno5,-seCcpiounrrttiienldelattsihaoamntplevdsiiarle(sc5)tancadnodun1t5FiCmn-lg143Ai-qnu1jaqsCuoaluserli'nvega isadded.
tsPhaaemcpkladerarsdk M(ob6d)ee.flore3A3ll8c5ousnTatrmiipnl-geC.sarbweArlLleiqurcioadodlieoSdmceitntrtoiiclrleafatrniiaoglneyrsaeStspoercwetrrteoemmepdteoernreat2uu.rseinCgionuanting
eEfxftiercniaelncyStafnordaredaiczhatsiaomnp)lerawtasiodmeettehromdi.nedTobycaulseibroaftethetheAESext(eAruntaolmatsitcandard,
wi(entrtheerreneraelcvoitushnttaenlddoawradlAoESnwgasrwaitatidhodsedaantsdoealtsehedrleeecsttwaeindtdhasradhm.pilgehDsatraaftriowomesr)et,hecoalngdlreocuttpheedosfeonssaapmmuppnllceessh
Rteaspeearacnhd with the
pBDiraotoalcoegsPisrceoadclesbysAiunttgohmeaLtCaiIbcCora1Et7xo0tr0eyr.nCaolmpDuSattteaarndraeSrdyduscittzeiamotniionntothcedopmmp3utweaCrsentaprrcaoclgormapml.ished
Results and Discussion
hcreoesnutlertnestsulaatffstteerrof iitnnhtterraavvleeinnvooeuur,ss
yranine
t
pdloassimnag, wiatnhd dosing with
rFFeCCd--1954b-3l-g'g1`dCacraeerlel sshahonwoanwlnysienisn TaTfbaolrbeleca1;r2.bothne-14
Cblhoooldestcell rats. For
cFaCr-b95ot-nr1ge%}aCdt,mecnmoenatnecnatcuhseofdloresatbydortehacmrieFnaCes--e3t5r-ie'pamtCeeadanndraltiFvCe-cr1a,r3b-oplng-s1Cm4ad,ocsoeandncden-red
ot(fr0a.t33i.8ou,ng/sg7)a.in7n,irneleapi-nrvtdeersree6an.(tt03e.d4afoluddge,/cgr)er,aesseppelcaftsrinovamelm(ye0.a.n9 r
ucFogor/nmtlrF)oC,l-1r4aa3nt-d,>c'roCen,dcembneltaornoadticoenlsls tions
cpfrlhoaomslmeamsetay(n5.1conutgr/omll),conacndenrtraretadtciaborlnobsoodn-o1fc4el2l,cso3n,(c1e.an8ntdraug2/gf)oldr,einprreelssiepvneetcrti(av1e2dl.ey1c.reuags/Tegh)u,s,
omrreeatdlabbocllhoiootdleessc.telylrTahmecionnlecaerngtetrrreaatdtimeoecnnrsteasoeeffftienhcetspielvaesltmywao recfdolunuccoeerdnotcratarhtbeioonlnsiveaarsn,d/cooprlmapsatmrhaee,idratnod
Pdtlehacasrtemaassoemfeluinoofrolctiahvreebrolnicvoebnrycecnfhtlorulaoetrsiotocynarrabfmooinrneibsotthrneotactomamefpnfoteu.ncdtsedmatyo tihnedicsaatmee, exhtoewenvtera,s
seThlhoiewnnirneasitnueldtTsavbiloaef cf3eacraebnsodn-bi1ny4cFhifogelucraeelsty1a.rnaanliyTnsheee-stmrefeaoanrteFcduCm-ur9alta5st-iCv(e75d.op9se%re)cdenirtsatso9f.5adreofsoeld the mean percent of dose eliminated via feces by control rats. For FC-143-1'C
"2Dpoawcnkearrsd GIrnosvter,umeInltlinCoo.i,s. Inc., 220 Warrenville Road,
COR2918
o FrCaihtgasul,reestthy3e.ranciahnreeb-otnmre-ea1ns4tecfduemcTailaltastainva(el4y3.ps2ee0sr)cerne1t5sulo5ft.s8doafsroeeldeshltohiewmnimneaiatnnedTpaevbirlaceen4ftecaoenfsd fibunyse CSilneidamtizmneeadnttebdloonfvdiaFcoef-la3lc8e-sq11gCbhyoannc-do1n4tFrCo-ml1n4cr3ea-pt1ps3r.CatdioTovhneusds, aTatfthteee. rdfeeo.rcaralecacoscmehpoaolnfeisetldyivreabrmy,inaepresna, Tarce increase in the extent of fecal elimination of corbonel. t`TTaihbenleeresb5uylatntshdeoifcnhoFthlieegsurtueyrirna3en.inaanTahcleryescaeutsmeudlfaotrraitvFeec-p9(e55.r-4c1%e%)nCtdiooofseadbdoousrteatsoenleiamrietnhaistrhedoswnofinitnhe pTerragieynetesoffordosFee-S1i43i-n1j0jcatdedasbey trhaetscoanretroslhowZnutsi.n TaTbheles6esauniasFoifgursehe4.urine FTahtescu(4m1l.a1t0i)ve4spesrhcouetnttohfreedosfeifethlsimgifnattheed pienrcuernitnegfbydocsheoleelsitmyisnaamtiende-tbyresthteed CCohnotlreosltyrraamtis.ne-turaestefdorrabcoethelFiCm-i9n5a-t1e4cleasnsd cPaerob1o4n3--iLdicindoswerdinerahtianthdoe the eSCosonpatercorileaslulTlyattsd.oufritnThgheethlneoewaerfrliyrsut1r0infaeTruoylddaeyxiscnrcperotesiatosnedoibsnyincfgne;ocraessinecclyeirmaiminniantceishotonrleesostfteydcraarambtiosnn-els STraeialtaebdleratfsormuucrhinaofrytehelicmairnbaotniegiyd 1soreallimienlaitmeidnatviiaonfoefcese,arbieon-isitno(turine PFlues aeggsT8)soisredshorwanvefoirn FFiCa-v3e5e-106.C doFsoerdPOTa-tsss-L{7lcFdiogsuerde s5ateensd afocrer 21 vGaeyrssusofonclhyole3s5t.y5r%amofinethetredaotsneenfto,r c8o1n.t3r%orofTatthse. dosTehehmaseanbepenerceelnitnaigneascedof CGoovnet.roTlonaaitnsi,ngarien itnheshbooduyt, th1e9%safnoer pcrhooptoersttiyornan(i1n1e4-)creaeathederdaicfeeenredncTeosv ifnor 5T3i/v0e)r.carhbeon t1o4talconctaernbten-(icsholeelsitnyisnaanciende (curreisnteedp,us5.4fe4c/e3s) byconFtOroolnis-13i5c:6 tiShneeeaddToosuxeaatnsfdois20c%o8,n4t%rroeolfspetTchaettisvdealstyeh.e fpoerAreeeceihnnotlaaesssetswyircoahfmidFna-s9ter5esa1gtg,eedinitrnhagesmIenaanndthep1e2Rr%ocdoeyfnt~ C"oensceonftraGtoisosnsrem(aSihnoilnegstyinrantihnee-btordeyntaerde, r1e2f.l1ectuegd/aincotnhcerorleslat2i2v.e3 mweaarnd)-liver vTheeiohitnsdivaniddua1livebrodyweiwgehitgshtsat sttimteimeof ofSacdroisfiincge. anadrethgegowinnsdiavliodunagl wibtohdy rCoirrees5ponfdoringPecoo1n4t3i-g)TicSdooupesn:reivns.TableGho7lefsotryrFaCn-isngs-idoiecs.dunsoredaprpaetsstanvdo in have caused a change in elas gain of Liver weidne in eieher experiment. aCnhdotehsastyrbaeemnineuseisd ianpphraonvaendsfoLro phruomwaentsusetheasexacrcehtoiloensteorfolxenloobwieortiincgsag(e2n)t eChseleestsyemsadimtisngininTamtasnvsith0FpOr-%o5motaendexFcC-r1e4t3ionsuopfporFtluotrheececronvcoenpet:. of esting
02919
i
References
(1) B`oThyelraanpe3u7t,icEAglpeproJaL,chGufzoreliaCnhloPSr:decoCnheole(sXetpyornaemj)ne:PoisUosneinags. a New Science 199: 893-895, 1978.
(2) cTornenatmWIe,ntBoofylaCnhlo3r3,decBolnaenke(KeRpV,oneFg)risTsoxiMic,ityHowwietlhl JCRh,oleGsutzyerlaimainneP.S: New Engl J Med 298: 243-278, 1978.
(3)
Behr FE, (Report)
JDoehcnesmobner ID2:8,
1S9y7n9t.hesis
and
Characterization
of
Fc-143-1%c
(4) (JRoehpnosrotn) IDN,oveBmebherrFE2:, 19S7y9n.thesis and Characterization of FC-95-1%c
(5) JToothanlsonCarJbb:on-1E4xteinntRaatnsd aRfotuetre oafSiEnxgclreetiIoVnDoasned TofissFuCe-95D-i1g'gCrib(uRteipoonrt)of December 28, 1979.
(6) JToothanlsonCpgJDb:on-1B4rtienntMaalned RanoduteFeomfaleExRcartestioanftearndaTSiisnsguele DiIVstrDoisbeutoifon of FC-143-1%C (Report) January 30, 1979.
C929z0
-5Acknowledgement SThiebinpsrkeipaoraftiPoanthooflotghye-To4%xicwo/lwocghyoliesstgyrraatmeifnuellyinskPnuorwilneadgGerdo.und Chow by L. J.
COR921
pre List of Tables ans Figures ble Li iH(nMveeaRrna,tsDPolsseatsmo3af1, FDaaCny9ds5-Raefdte10rB; laooCdhSoilnCegellsletyrC1aovmnictneoens-ettrraoeftaitopenod-,oof-3G.l4yeenbokn-:le Control, 3.5 mk) Wa $3107 7 26-27 Table 2: i(HneearRna,tsToFslaetasmo1ef4,Tbeaa-yns1d43sR-eegderLBicl:oaodCShiCnoegtllelestC1yovrnacsneeinvneter-oartfoiaoFtnOe-do1,faI1Ct3yi.gc5bomno-/ikeer Control, 13.5 make) NB 53102 F 38,39 ble 3: CrBIornlccercseavvtieyonrnoaursoifnDeToostetraeloaftCeFader,-b3o53n-.-14}1mcian(kHaPaaancCeostnotsirenoloRsfatsF3e.-5a9t5ncaee/rkesit)es Single 53108 7 20,21. ble 4: BInitcrraevteinoonusof tToosetalofCFaC-r14b3-o1%nC-ilny(feeacnes DionseRoaftsFaof-t1e4rv3-slienale C8rol5e9s1t05yra7mi3n0e,5T2r.eated, 13.2 no/ke) Contrors 19-5 marke) Table 5: CIBuniotclrreaesvtteiynoronuasnofinteToosteTarloefatCeaFedr-,bs-o1n3i-.c}4gmgin/(keUgarniCneotnotsirenoloRsfatsF3.C5waofnsate/Leklaree):Single S108 F 22a Table 6: GBIrrnoctlrreeastvtieyonenoaumsoifnbaTocsoretraeloaftCeaFdre,boo1n14-33l.-g31,7inna/(hueerasinneCoTnoitsnreoRroasfteF1e3a-.f1t5aesrm-airgkiseei)sngle E5107 7 3556, Table 7: BfToosrdeyRowaftesigFhoat-fs5ise-ralyciqcm,SoisniCgnhlgoelaanTsdnttyrBroaadvmyeinnoaewnsdTrLTeoiasvteeerdo:fWeiF3se.hstssm-et/gikyacrSa(cmrainfice Control, 3.5 ma/kp NB 33103 7 26 Table 8: BIfoosrdeynoaWftesiFgeha-tf1ts4e3ra-t1g%oTCgo,innidnigeChaonIldnecsrBtoaydvryaannsaiennede-LDToievveeesrtoefWdeiF1ge3hs.ti3sra-mpi,alSkeaca(rriefairce oneal, 13.5 ng/ke) V3 $3102 P 38. Figure 1: CrSuiemnoguallsea,tifovuera aBvxecnrToeeutnsitoynTeoaosnfeinoTafo-tTaFrlCe-aC5tae-rdp,gnTIC-3l.(d4semainnakFtaeo;cseeCsoonfatfrtoelr, a 35 ma/k) vaan of Five Rave FB $3103 P30.
02922
Figue 2: Figwe 3: Figure 4: Figue 5: Figue 6:
. List of TCaobolnetsimsaenddy Figures SFCiuenmtgulleeastiJvieraEvxCecanrtseeutssitoynDroovafenioTnfoetaFClt-rL4eC3aa-tLriebcdg,r-1l3d(.K3ienunmgF/eDkcogessse oaffeer a Control. 13.5 mo/xa) Wan of Five Rate. ND So10h P 0. SiQnungsllea,tijvreiraBvcernestuisonDoovfe oTfotaFlC-C9a5r-p13gCn-l(deainn Utorsien.eofater a Croenotarsol, He3.5 amoalkeas)tyrwaenainneo-frrFeiavteedR,ate3-4NBma5k3e3r02 P 26. CSuimngulleatipvyetraBvxecnroeutsionDoosef oTfotaFlC-C1aersbigipc-ld(eiannUrDionsee oaffter a CFoenottraoal-.Thc1,3.C5homat/evset)yrwaenainneoftrFeiavteedm,ate1.3.3NDng$/9k1g0:3 7 40. SCiutmaurlataivSejgaBieecreItnitornave(nUoruisneD+oseFeocfes)FCo-f95-TLygIaCl (ChoaarnbonD-olsde oGfantrreots,s3.5BELmaGkoel)evNeeyenamoifneF-itvreeanteetds, 3N.4$m3o1/0k5erP 20. SCtuimeirlataivSeiggBlxecreItnitornave(nUoruisneD+oseFeocfes)FOo-f143T-o1p3)C C(aNraabnon-Dlodse CofontFrCo-l1s43-1133.c5,maC/hnoal)esMteyarnanoifngF-iTvreeamtatesd', 1N3o.333a10/7kg3s40.
Appendix 1: SDeltueirmoinnatio3n 5o1f807CarBb4o1n,-4184+ Content of Fe-9s-tic. Dosing . ATaobpleendi1x + Corbon-id Content of Fc-95-114C msing Solution
= S107 7 44.
Appendix 2:
ATpiplenedi2x :
SDietaetrimoinnation 5o1f607Car7bo1n--4154. Content of re-143-Y4c Dosing Carbon-14 Content of Fc-143-1MC sing Solution 8 stor 7 45.
02923
ae
zone 1 iL(niM'veeRarna,tsTPalaetasmo2af1, FaaCyn-ed35aR1ey1dec,rBloaoCdhSoilnCegallsletysCIaovnnictneoens.etTrvoaaftsitoFened?-,0o5f-3,c.14iacrnbao/nk-as14 Control, 3.5 nakg
siver Sasa Ret Blood cells
rotestyramine-nastes
TE Rat nuy mber e se ms 97 7a me 09 11 oe 07 os 0.2 0.3 03 02 03
J
sei sexed 0320.
river Plasma Red Blood Cells
control
Tr Rat vue mber s Be 32 ae 07 ans 70 Te 62 ea 7s 21 2.2 Le 17 13
sean + 50
asks. sso lexos
2rotciaealrebxocpna-rr1eb4soane-cd1o4ncaescnotunrgcaetnsitqorunaitviaiorsnenetxfsporreosflsievFdeer-saas5n-g1u%grce/Fd3O;-obhlPo-lo1pdgincacells civaientornis
02924
-13-
Table 2 iLniveRra,tsPlatasm2a1, Daanysd aRefdgerBlaoodSinCgellle CIoVncDeonsetroaftiFoCn-1o4f3-1GaCrbon-14 C(oMnetarnolT,ose13.o5f mFgC/-1k4g3-13C: Cholestyramine-Treated, 13.3 mg/kg;
T
Liver
14.6
Plasma
70
Red Blood Cells 2.7
Cholestyrani ne-Treated 2 3Rat Num4ber 5 bean + SD 5.4 13.5 1.9 10.8 12.0% 2.1 30 6d 55 3.9 5131.7 1.0 2.4 2.0 1.2 1.84 0.7
control
7 7 3Rat Num4ber z ean + 5D
Liver
Ja 3s 2.0 17.5 16.3 2.3162
Plasma
19.9 23.5 10.1 8.8 10.7 14.71 6.8
Red Blood Cells 6.7 7.0 2.3 2.6 2.4 4.22.4
21i0staelxprceasrsbeodn-1a4s ucgonecqeunitvraalteinotnsfoofr FliCv-e1r43-a'g'gC/rge;d pbllyogomdacells ecqauribvoanl-e1n4tsc/omnlc.entration is expressed as ug FC-143-' C
02925
ae
D(hreentiToon ofotm1a2l3-1cytron-14aliantryreacneisnain eTasttaera,te3r.4amaSsihnegsleCoTnotteeoatvsenon5s mmaereioof o-ss-e
GpTtotoyenetion SToeas t anir a iemWares Ta E Wares
os oust
ao 2 9 20 0d. Lenn SE
on 0k ow es owdr soemme
I =
OT 10 0 00 eae BIL Ge 120 0 Bem
0m ak on en om omar em ln as oe se os
.
WE THe an ans SHSO ST Gm em Gna
om 05 0 oes bs oss 0 03 0 ous om oases
-
BEE ee ee nn wees as om en em on sas
" ~
GH2O Nm aE nn neem SO a 4 em So wees
an oa om eos os ames 0m ae se on La essen
on was
Ham am am neem 4% 4S em en sn sews
om ne oe ne on osm Le La es 1 Lae Lae
1510 3 en
B20 10 ne Ls sue de os ew 0m am eas
oe os oes om Lm ame om 0s om am om oseds
g wn eg
FH Tw WD ww AR mews o5w Ta% Tw e8n oiEr mew 07 TTT Tm
Bima sce expressed as percent of dose excreted during collection parton.
BarnettooneofofToTtEalACLagiTpC)n-iGrienstFyecreasminine-sraetestaefnter130a3S2ing9le Ionntriaovnensous13osaewhofaNFortes He
Fcaaortiwtaesction ros oo 1 = Pn = sn nae
TEBeesat embIer TE fo oar am as Am Se Nm Am Se 46 S50 nn nm AN am On mss 4% eas sm sas ne 4s Ems Am am Man em am 28 ne am 2% lee OEM ne AM am Nee Lm ND ne 22 mL ne am ae
o38 mw
6 00 wa wn
8Noonafecaxeassenxeprreensesneed as percent of done excreted during
TeanT Lewis adels amie esses em newer amen dees eer ewe nemem eas
collection
aT T Fa maT mbeer 00 am oa ow ao om as ea on of em om ne on om nau os ou ne am on om ons ode an on oe om ox on om oes om oa ode 0m on ox oor an om oe od on 0a om 0s 03 on an om oe om on a0 Sa 8 am A
period.
wa eases oasen oosas ous owen oom een oe eens oem eamar Gomes
re ono reas RET Crostyrasin3e.4_nravieoCnontoon nae,s ma
collection
To os os I = -
CT Golestyrasinetrested_____________
Leos 4m La Le Leen Go on ns em 0a eemsar Ge ee am ew oe emis J om em am oe ee Guede
EE __________Gemwel Lm Le Le Le Le Le Leo om am om Ll Lo em Lo La
Tw Lesa sees Lamas
La Lam Le La awe
oe or a ou nas Lee g wa @Ere mn
an eae an en am eames em am 0m om Ln esses am oem an eas aa eames ow oe om om Lm ome ais ea aa en am eam Ls Le LE Le La Ls om ear ean em es aimee La La Lp om Le Les om oem em ex en ames ne a8 an am ae news en ea am em oem ames Lm lw Le La aa Lesa aa em eas eae eur aes Lm Ls LmoLu ne Lesa wo TE wh e veBpee SEW eWeW e mRe Gewe waEew nEEe
Soata are expressed as percent of dose excreted during collection period.
te 6
nares osee Somers aEaa
Corlleection E CelespmmE imeteted T me hmwmm e a
0s Tae SA AD AT swe ue sae an te 6m ese
ast
1 SN an am sw sme ne as wm Se sm sna
=
ne Lm no ee enn 0 na en le oe sma
=
Mom Lm Am
same en nM Ge 900 se ham
-
LOS Al ae el omar slo wm ee Tae sa een
-
B03 ne 29 20 ame sa ao sa ese as sss
se
Lm ne Lm 26 nea an ne Se Gs sn esses
or
Ls aN La Le Lee an ne aie ae sm mee
-
1am ne an uD ames aa ew ew eu ee ese
sn
1 ns Lm Le nee ee sm se sa sn seen
nee
10 Ln Lm Le Ln Lew 6m em 59 ee sm see
o wa
RB HB S00 MES Gs 6 es Te ers
8--
81] 2awa axe cpcesse an escen of dose acer ducing cottection perton,
msn
emeiinneea(t9 vaseieyriattic(e9 mranageiInd Siegnfi(aet (9 QuoLafisvbeeorrayionneiltoeng 8@88
mbte7 Beondy 0tela1ht3a 5af 4maiang anod nDooty annd nLige ,Weh dohts ate Saecreirfie ncesfo,r Ra"t3e mattee apsainrglee Tontcatveneons
em term
Eo
aE
Ege r Try
ee
me wm am se om
osm
see om om ae 0m
0 gz an a0 wr wns
mw we we wm asa
Bs m0 m2 we as mapa Ha as 0 wa ie me
M0 10 D9 Da Me anemia we Ba mo des tea wae
15 ae ae az ae m0
2733 he aa ne va
es An LRnsiLinE DteAee CE T e -- -- Tw-- -- e ome---- ---- ir Fr . mv
32 Fim, Bat sacritice) au 17a 4 8
2640.4
an a a 20 a
840.4
Entroenaus beoseSoF FE35e-n1na1Cn2a4(naetnnaotonen,e o3t pea35-11 "Gratesiyranine
Cotocyanion Teste mtn
i oi
$
2
888
pA
CumaulSaitnisv]e
Figure 2 EIxnctrreatvienoonusofDoTtostalofCaFzCb-o1n4-3-11q%,Cin
(FeeacnesDoasfeter
of FC-La3 tic. Chotestyramine Treated, 13.3 mara: Control,
13.5 mg/kg) Mean of 5 ats
100
s
5 3 i8 : 2s
coi: 54% Days Fost bose To
ana CThroelaetsetdyrahmaitnse -
ano contol Rats
12
02933
.
mgTa ietiinmsstoen omfoeswearg SSaetEeor n SIgerireRahe
FT 83g
.A g
2
i
:
3
wo.5.40
i
.4
ermine
T
Ss
J 0
15
0
BE)
Figure & CumaouflsaitPnigevlneetaEI:xnctrrCeartvoielnoeonsutsoyfrDaoTsmoeitnaeofTCrFaCe-sa14tb3e-od1%,nc-1il5ng.3(Ue2ra6in/nke0Droasteter
Control, 13.5 naka) Hoan of 5 Rats
7s 6.650.9
t
Control Rats
Si$
i
ass
i:
Chotestyrfaonine-rreated
32
0
c 1 z 3 Daays F5ost bose
0
18 02935
rious
Comtative Excretion (rine + Face) of Total Covbon-14 ate a Sinaia
CIhnottreasvernaomuisnsDoesestoofrs,ee2l4emdis(sMeaCnoDnotsereof 3F5e-w5a-nca;
so
etertyminereese mats
3 i
i
mena
Ci.
-38 &&8
F
S
10
15
20
Figure 6 CumFilaetiSviaeng,lEexcrIGentteiroavneean(coyVuresainnbion+seeFeTocrfeosbF)Ci-e1d4o3:f-L0T13g.j3alm(oCrarecanbm:onB-oc1osndeteAonfftt,er
Sine Mean of 5 Rats
100
0a.3e 4.3 rolestyranine Treated
I.
ase.
3
Bneror
&
)
: 2
2 CES
34
Says ost Dose 10
15
COR957
ae rormuoax 1
Determination of Carbon-14 Content of FC-95-1%c Dosing Solution
uRriasahuesseCpiorriiilsoTgEroerweatecroeendaolamsibiiimoenvsregorspfoofipwaatratthteetseo,kptisGptfehteatieearFdceC:hc-t9doo5yfa-d1tinCh1teend.do1sc0oio4fnm1gewiaastnmoegalr.ut5v0iiaosnnida1onv1as5slinSadsnuaeomtfp1sl0.edsl onTfoaeuervnessiisng2st.inthgCeo.rhrsrepecestcitovrniesalswseervveeivrmieatydseruipfsaoerrseddbyacvSkiegncraoru2mn.id5ne2ac1ntd,ocfotmhueentthivanengro/le3f0fiinrcdiie7n.we5crym1 $Ci7uh5l3eenmtpaeosr1.3r2e1Ts0oasmyaysotELfa saro"elnulstsihooTnwoncoimnnatnAanpipneidnnadsgeix9o-f5T1e3s3l.au6cim1.aonfghFefEo-rSsoAtvhgeaLtIEhnweihnliieeshstee1rrsed Fmd estan tate ana 325 na/hs for she comers Tees
21/1 wicropipettor, Lab Industries, Berkeley, California.
Blew mgiand welesr, moston, assschusetts.
Sapaified TSS: 25.2 g PPO, 1.01 g Dimethyl POPOP 2nd 3.8 Liters Toluene.
ZiFrusesofa? nhte1e7n5sspveesceififcountdivcoitbye sseutiesrabmlienstsiooinve(n4o)s:cineillents for SpToeacibfeiecn raecptoirvtietdy (=470..459 uCi/mg. Specific activity determination
02938
a APPENDIX TABLE 1 Carbon-14 Content of Fc-95-114% msing solution
TTT
uciTo/a 2.A0limgler
0.50842 0.5012
0.52842
0.51622 0.50642 0.50982
50ucWil/2A.l0iqmulot
0.5m 0.53752
0.52082
0.52992 0.53832 0.51552
Overall average = 0.519410.0128
4509.51u9ci/mg = 1a33mg2.0m
22 sample prepared with Aquasol.. 2 sample prepared with urss.
02939
. repo 2
*
Determination of Carbon-14 Content of re-143-1% tosing Solution
CeTJeuatnsat"aUEpiheraekilo3edr0euUate1soeaIadholisaieitqanourgstoosfopfiscpuarecrarhstos,rSpefipttehttehdteieprdce1,-c1t4losh3yn-d2ai%nn1dt2o1d0os'osofimsenwtgaiatnlsegiorqluuvotaitinnsode.n:1w5ahsmSgxsasofmedpmplsAeqimsdnaisnogr TPeeaertieEctivteaorneascbteiveevrpiees,ryemadsdiewr.ietsfhdory3GD1ua5tceHkrIrmoiounfnetdnote,acnhadtnhaeelowuen1it2/di3ng.70.5eafLmfticwohiFeencHcyHilCsaunedI,A.CesSs:ing the TTEealoikee traeetwihoonm cinonhteaphienniidningn 2dT11aE5e4Loif3.1o3f.T2heFmCgfoa/3gkdsg3-LfgoiqrcmithmhiiesccheCrreo1s3tese4at.cr1hea5mtai0tne-in Cees Tae ina 157s Ras or the contaon roca.
21/1 Micropipettor, Lab Industries, Berkeley, California.
Brew msiand mclear, ston, Massachusetts.
modified TSS: 25.2 g PPO, 1.01 g DimethylPOPOP 2nd 3.8 Liters Toluene.
rFqueasio1? a4nddurHiTnSgS vsepreeciffiocundacktoivibevysudiettaebrlmeinascoilovnent(-3)s:cintiLients for spoeecibfeiecn aTcotpiovriiteyd (30= 0.507 uCi/mg. Specific activity determination
02940
-25APPENDIX TABLE 2 Carbon-14 Content of Fc-143-14%C maing solution
uCiTo/w2.Ali0quot m1
213122 2.06932 2.15882
2.08842 2.08382 2.00852
Overall average = 2.134410.0495
3.5027.13u4ci/mg = a2 m/20m
5u0ciul/2.A0limq1uot
2.12128 2.18672 2.15002
200022 2.21082 2.m9
2a sample prepared with Aquasol.. 2 sample prepared with wrss.
02941
