Journal of Medicinal Chemistry - American Chemical Society

Jun 4, 2017 - Aletabolism of Tranylcypromine-CI4 and dl-Amphetamine-Cl4 in the Rat. JOHX J. ALLEVA'. A'csctri (h tirid Dez.elopitie,it Dizision, Smith...
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Journal of Medicinal Chemistry J

@ Copyright 19BS b y Ihe American Chemical Society

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76, XUMBER ~ 6 ~

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~ KOVEMBER ~ 14, 1963

Aletabolism of Tranylcypromine-CI4 and dl-Amphetamine-Cl4 i n the R a t JOHX J. ALLEVA' A'csctri (h t i r i d

Dez.elopitie,it Dizision, Smith Kline & French Lnboitrtoi ies, Philadelphia, Pennsyluniiin

Received June

4 , 1.963

.\bout 4'7; of injected trnn?lc.),proiriirie-~" (label :tdjoininy benzene ring) was excreted unclianged, and :ibout 125; \viis excreted as hippuric acid-C't in the 24-lir. urine, which contained about 72% of the injected C'4. Corresponding values for dl-ampliet*Inine-C" were 15, 2, and 7055. Four additional urine CI4 metabolites of trxn!.lc)-proniine-C" identified.

: m i t w of dl-x~nptiet:tiriine-C:~'were demonstrated in paper chromatogram but were not

f~~rc~is-~-l'lieiiylcyclopi~opyla~iiiiie (t,raiiylcyploiiiiiie2) was syiithesized by Burger aiid I-ost3 n-it,hthe iiiteiitioit of iiicorporating into a single niolccule the aiiesthetic. cyclopiopatie, and the ceiitral stiniulaiit, amphetamitic. T h e new conipouiid was fouiid to be a potent iiihibitor of nioiioaniitie oxidase4 aiid an effective antidepressant iii niaii,,i 111 the piwelit iii\.est,igation the nietahol~sni of ti.aiiylcypt,oniiiie \vas studied with pai?icular iiiterest centered o i l the fate of the cyclopiupaiLfritig3siiicf siicii kiion-ledge appears limited to cyclopinpatie and its methyl, ethyl, aiid \.iiiyl etliei,s, all of irhich are believed to be metabolically iiiert aiid are excreted uiichaiiged.ti The preseiit results iiidicate that tratiylcyproniiiie is nietabolized esteiisively in the rat hy pathways includitig clcal-age of the cyclop~~opyl riiig. Because of the close structwal similarity of tranylcypromine aiid aniphetaniiiie, a coniparati\.c iiietaholic study was made wiiig t,lw C14foixi of each coinpound, labeled as fo1lon.s'

Methods Purity of C ' Compounds.-'l'raiiylcypromiiie-C' 1 sulfate behaved identically with an authentic st'andard (1) Enriocr.int, Cpctirin, Ilivision u f l'liai~i~iacology,r o o d a n d U r i l .\+ illinistiation, \\'asllingt) 31. C'. I'rtrrsrn a n d .J. 5V. AlcBrayer, 4 m . J . I'sychiat.. 116,6 7 f l 9 5 R ) ; 0. I'elzirian, l'suchiaf. Quart., 35, 261 (1961); h l . L. L u r k and H. AI, Salzer. . l m . J . I'suchial., 118, l . i 2 (1961); -1.-1.Bartholonien-, M e d . J . Australia, 1, 6.75 (1962). ( 6 ) R. T. n'illianis, "Detoxication 3Ieclianisiiie," J o h n Riley B: Yonti, I n c . , Xew T o r k , h-. 17., 1939. (7) Tranylcypromine-Cl4 and dl-ampiietaiiiint~-C~' sulfates were synttiesized by Drs. D. \V. Blackburn and .J. W. Wilson, respectively, a t S m i t h Kline R- French Laboratories, Pliiladeliiliia, Pa.

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throughout ultraviolet spect'roscopy, paper-strip chromatography employing ninhydrin, and CI4analysis after paper-strip chromatography. Cl4-Purit,y was over 99.9L7,, and t'he specific activity was 3.81 pc.;'mg. dZ-.ln~phet~aiiiiiie-C14 sulfate was analyzed by the third method only. C14-Purity was over 99.9% and the .specific activity was 2.78 pc./ing. Recovery of CI4 in Urine, Feces, and COs.--The Clll compounds were dissolved in water and were either i l l jected subcutaneously (s.c.) bet ween the scapulae into inale albino rats (205-215 g.) or were given orally by stoiiiach tube to similar rats (240-262 g.), rlliquots of urine plus cage washings, collected daily, were dissolved iti "aclueous" phosphors and were counted ill a l'ackard liquid sciiitillation spectronieter. Corrections for queiich were made by recounting each sample with internal standard. Fecal pellets were dried for 2-3 days in ~ C I C W over KOH, weighed, powdered in a Kariiig blendor! pressed into plaiichets, aiid couiited at infinite thickness in a gas-floxr geiger counter. For comparison, aliquots of dose solutions were added t o unlabeled fresh rat feces n-hich were then treated siiiiilarly~ Direct proportioii was obtained betn-eeii added atid measured activity . Expired COZ n-as aiialyzed for C" in t'1i-o inale albino given tranylcyproiiiiiie-C1~. Ininiediately rats (22'3 I$.) after S.C. iiijectioii, each rat was placed in a plastic chamber through which COz-free, liuniidified air was drawii aiid bubbled successively through tn-o columiis in series containing lo yo SaOH. Carbon dioxide was precipitated as BaC03 which n-as suspended in "nonaqueous" phosphorg and counted. Urine was collected quantitatively and analyzed for Cl4. Paper Chromatography of Urine.-Ten male albino rats (300-330 g.) were each given a single S.C. inject'ion (8) 2,S-Diplienyloxaaole (10 g.) plus 160 g . of naphthalene dissol\-ed t o 2 I. a i t h a solution of toluene-1,4-dioxane-etllanol (1: 1 : O . C \-./'v.). (9) 2,.5-Diphenyloxazole (0.3%) plus 0.01 70 1,d-bis-2-ij-phen?-lozazolyi)benzene in toluene.

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