Species Differences in the Metabolism and Disposition of Antiviral Nucleoside Analogues: 2. Zidovudine

Abstract

Preclinical and clinical studies on the disposition of zidovudine, a thymidine analogue with potent activity against human immunodeficiency virus, identified significant species differences in the metabolism and elimination of the drug. Zidovudine was extensively metabolized to the 5′-O-glucuronide in man and other primates. Rabbits and dogs were intermediate in their extent of biotransformation to the glucuronide conjugate, whereas rats and mice excreted the drug largely unchanged. Decreased metabolism was compensated by increased renal elimination, such that plasma elimination phase half-lives for zidovudine were similar (0.6–1.1 h) in all species. Rapid and extensive absorption and considerable penetration into tissues were also observed for all species studied. Only in the brain and testes were drug levels less than in plasma, although effective antiviral concentrations of zidovudine were achieved in brain and CSF. This review summarizes the variety of studies of the absorption, distribution, metabolism, and elimination of zidovudine in several species, including humans.