COMPARATIVE METABOLISM OF THE ANTIVIRAL DIMER 3'-AZIDO-3'-DEOXYTHYMIDINE-P-2',3'-DIDEOXYINOSINE AND THE MONOMERS ZIDOVUDINE AND DIDANOSINE BY RAT, MONKEY, AND HUMAN HEPATOCYTES

AZT-P-ddI is an antiviral heterodimer composed of one molecule of 3'-a zido-3'-deoxythymidine (AZT) and one molecule of 2',3'-dideoxyinosine (ddI) linked through their 5' positions by a phosphate bond. The metab olic fate of the dimer was studied with isolated rat, monkey, and huma n hepatocytes and was compared with that of its component monomers AZT and ddI. Upon incubation of double-labeled [C-14]AZT-P-[H-3]ddI in fr eshly isolated rat hepatocytes in suspension at a final concentration of 10 mu M, the dimer was taken up intact by cells and then rapidly cl eaved to AZT, AZT monophosphate, ddI, and ddI monophosphate. AZT and d dI so formed were then subject to their respective catabolisms. High-p erformance liquid chromatography analyses of the extracellular medium and cell extracts revealed the presence of unchanged dimer, AZT, '-azi do-3'-deoxy-5'-beta-D-glucopyranosylthymidine (GAZT), 3'-amino-3'-deox ythymidine (AMT), ddI, and a previously unrecognized derivative of the dideoxyribose moiety of ddI, designated ddI-M. Trace extracellular bu t substantial intracellular levels of the glucuronide derivative of AM T '-amino-3'-deoxy-5'-beta-D-glucopyranosylthymidine [GAMT]) were also detected. Moreover, the extent of the formation of AMT, GAZT, and ddI -M from the dimer was markedly lower than that with AZT and ddI alone by the hepatocytes. With hepatocytes in primary culture obtained from rat, monkey, and human, large interspecies variations in the metabolis m of AZT-P-ddI were observed. While GAZT and ddI-M, metabolites of AZT and ddI, respectively, as well as AZT 5'-monophosphate (MP) and ddI-M P were detected in the extracellular media of all species, AMT and GAM T were produced only by rat and monkey hepatocytes. No such metabolite s were formed by human hepatocytes. The metabolic fate of the dimer by human hepatocytes was consistent with in vivo data recently obtained from human immunodeficiency virus-infected patients.