IN-VITRO AND IN-VIVO DISPOSITION AND METABOLISM OF 3'-DEOXY-2',3'-DIDEHYDROTHYMIDINE

Citation
Em. Cretton et al., IN-VITRO AND IN-VIVO DISPOSITION AND METABOLISM OF 3'-DEOXY-2',3'-DIDEHYDROTHYMIDINE, Antimicrobial agents and chemotherapy, 37(9), 1993, pp. 1816-1825
Citations number
37
Categorie Soggetti
Pharmacology & Pharmacy",Microbiology
ISSN journal
00664804
Volume
37
Issue
9
Year of publication
1993
Pages
1816 - 1825
Database
ISI
SICI code
0066-4804(1993)37:9<1816:IAIDAM>2.0.ZU;2-1
Abstract
The disposition and metabolic fate of 3'-deoxy-2',3'-didehydrothymidin e (D4T) were evaluated both in isolated hepatocytes and in nonhuman pr imates. Rapid formation of thymine and beta-aminoisobutyric acid (BAIB A) occurred following incubation of hepatocytes with 10 muM [5-H-3]D4T . Substantial levels of tritiated water were also detected. Exposure o f cells to D4T in the presence of either 1 mM thymine or 10 muM benzyl oxybenzyluracil, an inhibitor of dihydropyrimidine dehydrogenase, decr eased intracellular BAIBA levels by approximately 89 and 63%, respecti vely. Concurrently, [H-3]thymine levels increased two- to fivefold. Th ese results are consistent with D4T being cleaved to thymine, which is then degraded to BAIBA. A similar metabolic disposition was observed in monkeys following administration of 25 mg of [5-H-3]D4T per kg of b ody weight. BAIBA, thymine, and tritiated water were identified in pla sma and urine. Approximately 50% of the administered dose was recovere d in urine within 24 h, with the majority of the radioactivity represe nting unchanged drug. After administration intravenously or orally of 25 mg of [4-C-14]D4T per kg of body weight to monkeys, a novel metabol ite, designated X, in addition to unchanged D4T, thymine, and BAIBA, w as also detected. The sum of the three metabolites and unchanged drug accounted for virtually all of the radioactivity in plasma and urine. Thymine and X exhibited kinetic profiles similar to that of D4T, with plasma elimination half-life of 2 to 3 h, whereas BAIBA levels remaine d constant for extended periods and declined slowly; this metabolite c ould be detected 24 h after intravenous drug administration. Mean oral bioavailability of D4T was high at approximately 70%. As observed in the [5-H-3]D4T study performed in monkeys, approximately half of the a dministered [4-C-14]D4T was recovered unchanged. The remainder was not recovered in urine or feces collected up to 30 days after drug admini stration. These data suggest that D4T metabolites are further metaboli zed by salvage pathways and/or converted to biological macromolecules.