Document bBwRnBvngKQR61grezy0N6M9Z
AR 226-0455
oe
wa
:
JAN 171980
AbsoArfptteironaoSfinFgCl-e14O3r-al'%Doignemacs
December 28, 1979
Conducted at:
During:
Conducted by:
Report by:
Reviewed by:
SRuibkseirdiLaarbyoroaftorIies, Inc.
St. Paul, Minnesota 55101
October to November, 1979
S.J. GIbson and J. b. Johnson
SeanniesorD.8il,ieoinnisocna-l Pharma4coloBgaitOseQe
M
an
agFeEEr&, `br
ugGhaHr,etabPohlD
Hid
Ise
[Ta6t0e
02855
5
BEST COPY AVAIl ABLE
sumary
ooASfFfetooerrrthaaalalnsci,ancrgablTroervnoa-unoiptrheaelirfodrfdoomasttehprl2eoa8efsmhmFaoeiu-sr1s4r3a-t"si,cau(tLmeaIensEsdeo]s2e3,%3o1f1.0tchmeede/tktogot)taallIn 13 8.8 sare!
CO2Z856
Antroduction
/
57158M0m,,* Fetuy
* Denotes Position of Carbon-14
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Coarrbotn
ca
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Hethods
Radiolabeled re-143-"e
hsrIeeppccenucrsisoefaliric1bs2om2an)c-ts1tih1uv5dil0ta.yb5e0l7o1fIsutahCtiisntghl.eot coTahfrF ebonFeyCl-1iac3a-l r1bkocn (wR(aisnekeerfoaubInosgvoetoopsoetorhuIcntvuernet)o.ry The Sseeppartaettelyc.har(a4)ctieesr;izadteitoanl,lsanodf rtahedisopcahcaiifciecl a`cptuirviitytyddeeetseremriinantseliutooint,waabslerefpoorrted Animals
GTMGrrarooloumenn2d3C00h04Cahroltew0essaa3n9aRd8i"vw5ea,Crt2?em0re5C2aDn fr3oa6rt2s,194.theonTuhrweseekrpsartiso0r1wde,tvoewdeoorspeiIacntgoeunddiFftarieeo.enesadacdctoweiingdhitvsiduraalnged
Dosing
before and mediately after sosire ess to Purinak
Gah
dove
aan
oF
fasted,
FC-143-
at
14.
41412 mg FC
waThsewdeoisgehewdasIm2m.e0dimaiteolfy
before
o 0-92
NbaeCilngsosliuvteinona
single oral
containi
STereide]s na
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vvaass dfeatierreninbeyd ibnyvedritriencgtbcyouhnatndi.ng T(hseeecAaprapsdeojnnud-siitxhings| onvcoenvseoutrimmddos0i.n9g% saocllu,tion
Sample Analysis for Carbon-1k
ppoarreess noyfiiwnatgerof(wf/ewc)estoandonetipsasrutesofwasbiodloongeicIanlWmaaritnegriballendetrnse hboymoagdedniantgesnine
2
2
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ooogen
.
opyerefarwienigghetdhe icnotnoe SToamrppiuessti(rgrmoongentahte
caonmdbuastdidoinngc1o.n0es9 oIfn between samplings.
tthreiphliocmagtaenaotne.* Urine, red blasd
t`ocpo-reloracd.ingtakbeanlantcoe carts. an
JSiarvaees arouse)
idna,snheo"24 punting.
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the
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GSnnttadrrznaarr.nd| Sinrained
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SCmaroniontratacr8aedt{ecerafnnfatilecrineSantlcaynsdtafarondridzaearaetdcaihcowhnas)sasmasprmdlapdetleeidwoawmsaestdhecotadel.rcmuilanToteeddc.abjylpvFreoaerteoefxtthcreherxniteesr(anmAaoullteos",,
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Sample Collection
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Tsomatla)] vend
paipteecideo;s;no.sp@lehIenenp,aadrddiiingtieizsoetndivtteoubetp.riaacstnPelpalasunmsda ansestine,
wraesd pblroeopdarceedlpirnoemoetriIsnmtbmueyrdiiantee,ly contents. (espmages. stoma
Tfoorrcacarrbboonn.-1f4ioamnaelalycashrigseo.f itnhteesttihnree,e arnatdscoIlnont)h,e a2kndanrdem4a8inhdoeurrsutpecsotrooneicshe, groups
RResueltssaanndudDiDlissccutusssison
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t--o_t--al carsbeo,n-alt 2ihn hfeocuerss aanndd d5i.g03estaitve48throaucrts.plusAsco3n4tohnoeusrs,fs tneheiTinmeaatyns ts4ou.nn3d3oosfe.
2
2
Packard Instrument Company,
New England Nuclear, Boston,
Inc., 2200
ass.
Warrenville
Rd.,
Downers Grove,
Illinc
COR858
- BEST COPY AVAI Apt SToSfaitmttshheerieFreeinslhlitnhoef7d8eilglieimskitenilavyteirotenrp.arcets"eTnthteissdsausteyasstoferrmoimcinatlhlteyhe4a8dbisghoeorsubrteidvpeecsatrtrbaaocnt-1tporrefseecnets
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OJcFmtopttahteyienacueTomoa 1tcaors%g3e)fvraoomrlubcmoaenr-chlaohssmssoegxhdeconarmateotatgeeesadnrawetveeirnsaeotwunreeasscedsa1scfecFruiyrcaetitnesdofhroomtroageceonnieedi.etdy
oCfissusund The
TEohofitgehteehnrectdreoastee1-oa6ft3)e2x4c(r1h)eotuoirrosnafontrdhanF1-4t8.h80a7to-fTghhtcrheearxvdeo2ds4einfaheorotuwraF4ses8-9ob(5no-u1tt8h.e
sTvheirscsis 5!a nmeuch ae 2k pours!
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2F1ef2-.4gSshd-eatyhoscs,peostfouInvddoIsnespfloerenFc-a8t072-414anc.d
4(82)hou1rps 1p4osstimailraer
dtoositnhge
served w3it0h.2%
ar
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arnedte4n8tiohnouorfs
acafrtbeorn-a1hsinIgnleredorabllooddoseceorfiaFe-183-18,
i"vtheelrye.
1s
Thus, at 24
no selective
a6t6,roeT51s2A,hoSwA2nkL,Sin48p,Traob9nl6,eana3a.lndysTiAhsheofhloougprlosafsammfetaesnramcopolnescsienngftlrreoamtorigaorloudvpeosrseofofthFreCe-14r3a-t1s4cac, 2,
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References
l arbon-14 after oral dosing with fesoi"
(1) J(oRhenposrotn),Jb:OctoAbbesrorp26t,ion197o9f. Fc-95-14 in Rats After a Single Oral Dose
(2)
Johnson 40: Extent and TSoetpatlembCearrbo29n,-14197I9n. Rats
Route
After
of Excretion and
a Single IV Dane
Tissue Distribution
of FC-807-14 (Re
of
port),
(3) J(oRhenpsorotn),Jb:JulyAbs1o0,rpt1i9o79n. of Fc-807-14c fn Rats After a Single Oral Dose (4) B(eRherpoFrEt,, JDoehcnesmobnerJD:28, Sy19n7t9h.esis and Characterization of FC-143-14c
02859
a LT Liissttoa off Tb ableslaannde FFiiggus urrees
Table 1:
Table Zi
Table 3: Flgure 1: Appendix Table 1:
fTepbpleend2i:x
22P4e0r0acnedn0tF4M8FaecM-oo1vu4er3rs-y1,4PoosfttoTDootRsaaelt.s Ca(NreBbaon$n2-51D84o8s;eA,f'tpe.1r12.74#. mSairnigel)e oOrral
Comparison
to Plasma
of
Total
Carbon-14
Contant
of
Red
Pood
cents
After a Single Oral
N(BMa5a2n58D4o,se,5. 1215..0 m/kg) at 24
Dose of FC-143-14 toRats and 48 Hours Post Dose.
2ZC4oo.nrc4en8n!,tr9aS6tE,ioaancndhofe1,4CkaraHbaoounnr-s1D4PoosIesn,t RDa1ot1s.e4P.lmags/NmkBag)ASf2ta8ee8r.1a:'p2S0i3n08g!)le 1O5ral
Mean
Oral
CDoosneceonftraFtCi-o1n43-o1f4cCar(bMoeann-1D4osIen, Ra1t1.4Plma/smkeg)A.fter
a
Single
Determination of NB 51807, p. 32.
Carbon-14
Content
of
DosingSolution.
RSpeickoevderwyitohfFTEo-tTaol3-CTahreb.on-u1e4 afrcommeBlaarnk k8B!iological Samples
02860
BESTEAgyp
Table 1
single
Percent Recovary of
oral bose of FC-143-'C
Total Carbon-14 After
to Rats (Kean bose, 11.4
Ee)
at 24 and 48 Hours Post Dose
x Yorer
' 2 3 Hean u 5 6 Kean
ToPTosm itmeDose r -- Carcass. m -- Trac p gestive -- a --
(Hours)
Conttentlsus Feces Urine
2 2
56.04 60.30
2.58 2.62
dg 13.98 3.43 7.3
2%
62.58
2.53
woz 6.29
59.84
2.58
a2
9.21
[0
54.38
1.68
5.32 15.54
ww
51.60
I)
"37 17.20
"
55.04
1.80
5.32 1.69
53.67
1.66
5.00 wa
Mtteeexantnn).)t?otaRlelreycov8erryerliesct7i5o.n9 oafndi75.8Tnhfeorrontthe i2nhaccaunrdac4y8 ohfourthegrcoourpe,s.spdeocrtsiv(erloy;
02851
5-
Table 2
.
RCeodmpBalroiosdonCeolflsTotaanld PClaarsbmoans-A1f4teCronateSnitn?gloef
Oral Dose of e-143-" to Rats (Mean bose, 11.0 nak)
#t 24 and AB Hours Post Dose
Numnbater
)
2 3
Kean
4 5 6
Mean
Tine
Pons ore
2
24 24
"8 "8 48
RCeedlBllsood 9.16
14.80 1h.ks
lems
6.34
60.68 48.54
10.20 12.69 7.50
50.66 42.76
43.72
2 Data are expressed as ug equivalents of Fe-1u3-Yesg.
RPatilo Need aBlood
0.20
0.24 0.30
rs
0.20 0.30
0.17
om
02852
Table 3
After
a
Concentration
Single Oral bose
of
of
Carbon-142
FC-143-'%
In Rat Plasne
(Mean Dose, 11.4
mg/kg)
fploousrts
Rat----
Av+e5ra0ge
1
27.75% 30.04 #2
2 Toes
48.40
41.58
6
4.67 58.29 64.62
12
63.8 59.39 7.0
2
49.89
64.53 53.66
"8
54.63
5.7
--
9%
3.91
a2.2 2.73
I
29.87
2.79 29.51
27.30 2.98
52.80 + 13.94
62.53: 3.67 66.78 9.21 56.03 7.61 50.19+ 6.29 35.692 6.38 2.72: 30
# cOaautisvawleernetsobtoafinFeCd-14b3y-14jCr/emclt ocfounptliansgm;a. data are expressed as 4 Three rats were dosed and sacrificed for each tine interval.
Scaomupnlteinwga)swavesrynohtemuosleidz.ed; data for this sample (obtained by direct
c02863
"
p
i
&
5
ju
3
7 iL, z
5
2
Figure 1
After
a
Mean Concentration Single oral bose of
of Carbon-14 in Rat Plasme Fe-143-'N (ean bose, 17.4
mks)
C( p=6h 64a -0.0! 006005 1
=
===(Least Squares Line) th = 115 hours (4.8 days)
so
A
O2864
o
T
3
77
36
Hours Pose bose
120
Th
ETH
Appendix | Deternlnation of Carbon-14 Content of Dosing Solution
IJasle eBatyoIrehtocadtotbirnagteodf ini 19 Ly and olx 50. u)
marl1a1ctqsru,oopttlshpewaetFrtCeo-r1p4si3p-de'it%rteedc.td"loysinIgntosoclouutnitoinngwavsials;
FFrCo-Vu1n4.d3-11n4dRCe raSolprrudenuatrdisynosdleetferfwniaircneeided,ancdydeadn,d, cousrirnegctitohnesswpeacrOienfeimc.emidsscoeffiourwlaobtyaerrokr:
TTheedanta gare Iota! 12 mg
osfhooFfwCn-o1lI4nu3t-Ai1p4opCne.ncdoinxtaTia`nbthileengyeI2.i./130T.0hoeuadilorwsoa.fssFdceaa.ilncTiuaslpattaerdeThe.dasracchh
Trhatoss.e 970U Of rats and 11.0 m"Tah/iksg Ifso'rs mtehaen26doavnedn4f8 5h1o1urmoSr/okugpsfoorfthe
L U1 Wicropipettor, Lab Industries, Berkeley, California.
2
sFAeCqp-ua3ar5sa-ot11e4lyw)ad.surifnogundspetcoifbiec aacstuiivtiatbyledestoelrvmeinnta-tsicoinnt(ltloenbte
for
reported
tSopebceifircepoarctteidvitsyepa=ra0t.e5l0y71.) uCi/mg. (Specific activity determination
CO2865
a
Appendix Table 1 Carbon-14 Content of Dosing Solution
$1/ im)
.
1.0393 1.0ug
1.0598
1.0427
1.0709
1.0473
Overall average = 2.100 uCi/2.0 mi dose
0Z:5O07ETu!Ci /mg4.1012 mg Fe-143-"c/2.0 mi
YE1/ T1g; e 1.0804 1.0365 1.0328 170655 1.oM7 1.0348
CO2866
"ne
Appendix 2
Recovery of Total
Biological Samples
Carbon-1h From Blank
Spiked with Fe-143-
Ihc
rFeees TERpaarsy For Feironih
boefoeentlotrae1l3poarctaetrdobotn(h-2e,143s)uf.irfoumrIcnaotmtohbmeussaetneddJatFecl-o8y0m7o-l'eYculaensg,
oaFFFoerBr-eBoFnoCyr-114eB4y3-s1tt4hoen,8s2ht0ohdueldcraargbboeovnaryrelyadoicflayrtboortnaalle1s3csealdarbbbeoylencTd-to, maaTpeneedtcFrtliohnuneeed.cinTcheulss,
of
total
carabnodn-F194 5f8rom186c,omibtuswtaesdanFCt-i1chi3p-a1thed
thas monnrecfoov"ery
would be realized.
coiaFnauglTsabceaatdsiarFreCs14d13i3-r1ge8cltelsydofsIoinutnrogrssecopillnuittciiaTotineastwieoorfne 1a0l }4q1u,os5e0d'4s1,ichancgal1i0b0raut1ed
SoCorro#pn'ne7lls8aaiUtnmnhmiae)).cas0m"efMeassnoddlyut1ci0oo0nntulaainnwdeadrpei'bpalealttniekqsu,obtieosldiocgdhieicrvraileatjhcreet:yse laaotcrocbeoonomnsbrcueospltllitiocinantees
oandd mthae FETUS
sioelsvenfTth1se1ececorolmlpbeaucpstetrei.donIBncloatnhneeks
wFelrieterdripeadperansdmofuctpaaosrseepseloglSereenteibtzuhedsomtwoeigtedhnates vials to omjcr
P[aEc1k8p3r-a1u3nCy Sdsaipcrihekcetsdeltyp.eolfleotnbesl'olwaoasgrclehcaoclofmsbtuhasettee1ds0:bpeiengsobteogeinanFriCn-g1,14030m-i1d8dCleh,ad
Tnb2yy3a7C0ceorrS oeuanrdE inganmd2eac6no0unrateriseunlgtssheofwffnircoim`ienndcAiypr,peectnpadaidrxcdernst iAornefciooenvrsesrCasormrmbaiudescitaiolo"cnu.floartTehde
c1o5n,t2a7i:n3i8ng FTheu-s1.43-cToRmcbusftoironcouIntsiang.suiItna'sble1iTqsaubeilaaess3a.ofinpyrcoeeyptpaurrsiitonn!rdrgceoscuaonmvptelererys.
C0867
">
Appendix Table 2
BESTCOPY AVAILABLE
RecoovferPylaosfnsToStaamlplCeasrbSopni-k1e4d Fwriotmh FFeec-a1l43H.o1mohganate
lo yi 111250g42 nn2zy
TIT + 4g
DiDirreectt Addition
sou
6a08n8 56918552
035+ 86
10 41 11u95g Nnesh7
TI7E + 24
Spiked and Oxidized 5041 55996694
57553742
B83 + 193
TZ x 100 = 1008
202 x 1=0350.3
Overall Average = 37.3
100 41 1122223834 1122115382
2207 + 70
100 1 111861869 11779983
TIT + 58
TE x 100 = 56.5
2 Amount of Fe-ju3-lic 2piking solution added. 2 bata are expressed as dpm.
02868
-16-
DISTRIBUTION LigT MoT. case 5. F. Chang 6. 3. conara Ho E. Prefer LI. Harrison T. Lo Xerley J.D. lazerte Lo 3. Maginr R.A. Neleon Re EB. Ober J. A. Pendergrass R.A Proxop AL. Rosenthal PA mbar P. Venkateswariy TDeMcGh CCeonmtmruanlicpaitlieons WF. Wittaan (Central Files)
218-2 210-2 218-2 201-28 228-2 218-2 236-1 223-65 218-3 216-2 220-28 236-3 230-3 220-28 236-30 228-2 201-20 228-2
C02869