THE DISPOSITION AND METABOLISM OF 2',3'-DIDEOXYCYTIDINE, AN INVITRO INHIBITOR OF HUMAN T-LYMPHOTROPHIC VIRUS TYPE-III INFECTIVITY, IN MICE AND MONKEYS

Abstract

The pharmacokinetics and metabolism of the anti-human T-lymphotrophic virus type III/lymphadenopathy-associated virus agent 2'',3-dideoxycytidine have been examined in BDF1, mice and rhesus monkeys, with ancillary enzyme studies carried out on tissue derived from both the latter species and also from human subjects. For the pharmacokinetic studies, 2'',3''-dideoxycytidine and its catabolic product 2'',3''-dideoxyuridine have been separated and measured in plasma, urine, and cerebrospinal fluid by a reverse HPLC method. For metabolic studies, tritium-labeled drug (labeled in the 5- and 6-positions of the pyrimidine ring) has been employed, utilizing an ion exchange HPLC analytical method suitable for the separation of the parent nucleotide from its mono-, di-, and triphosphates in cell extracts and in tissue homogenates. The drug is rapidly cleared from plasma in a biphasic manner (terminal t1/2 in BDF1 mice and rhesus monkeys of 67 min and 109 min, respectively) following an iv bolus dose of 325 mg/m2. This two-compartment open model is predictive of plasma concentrations during long term ip infusions in mice. Dideoxycytidine is predomiantly excreted in the urine as unchanged parent compound, although a minor urinary metabolite (2'',3''-dideoxyuridine) is detected in the monkey but not in the mouse. Oral absorption of 2'',3''-dideoxycytidine is rapid, with plasma levels approaching those seen after iv administration within 45 min in the mouse. Entry to the central nervous system is also rapid, but the cerebrospinal fluid to plasma AUC ratio after iv administration is only 0.026-0.040 in rhesus monkeys. Relatively high tissue levels are seen in mouse kidney, pancreas, and liver after either single bolus iv injection or long term (7-day) ip infusion. The drug appears in tissues mainly as the parent nucleoside, with its pharmacologically active anabolite (ddCTP) accounting for only a small fraction (<2%) of retained drug.