Intracellular metabolism and pharmacokinetics of 5'-hydrogenphosphonate of 3'-azido-2',3'-dideoxythymidine, a prodrug of 3'-azido-2',3'-dideoxythymidine.

5'-Hydrogenphosphonate of 3'-azido-2',3'-dideoxythymidine (HpAZT), a novel anti-HIV drug approved for the treatment of HIV-infected patients in Russia, displays some clinical advantages over azidothymidine (AZT). Metabolism in the HL-60 cell culture and pharmacokinetics in mice of [6-3H]-HpAZT (in comparison with [6-3H-AZT) were studied to elucidate the metabolic basis of its lower clinical toxicity. Accumulation of [6-3H]-HpAZT-derived products in cells with time, distribution of its radioactive metabolites among blood and different mouse organs and dependence of drug accumulation on the route of administration were investigated. The rate of accumulation of [3H]-HpAZT metabolites in cells was slower than the rate of accumulation of [3H]-AZT metabolites. [3H]-AZTMP was the dominating metabolite at all time points, achieving the level of 15 +/- 3 pmol/10(6) cells after 25 h incubation. After oral or intravenous administrations of [3H]-HpAZT, the (radioactive) metabolites were rapidly distributed among blood, stomach, intestine and liver and were not found in brain, muscles and spleen. [3H]-HpAZT underwent rapid and extensive metabolism, [3H]-AZT being the dominating product at all time points. Administration of 180 nmol of [3H]-HpAZT resulted in an AZT concentration in blood of 1-3 microM after 5 min, which remained practically constant during the next 25 min and did not depend on the route of administration.