Benzylacyclouridine. Pharmacokinetics, metabolism and biochemical effects in mice.

The pharmacokinetics, tissue distribution and urinary excretion of the uridine (Urd) phosphorylase (EC 2.4.2.3) inhibitor 5-benzylacyclouridine (BAU) were studied in C57BL/6 female mice by reverse-phase HPLC. The plasma clearance of BAU after i.v. administration followed first-order kinetics with a half-life of approximately 36 min. Other pharmacokinetic parameters such as volume of distribution (17 ml), clearance rate (0.3 ml/min) and the elimination rate constant (0.019 hr-1) were relatively constant over a dose range of 5 to 240 mg/kg when based on a first-order clearance model. Following oral administration, BAU was rapidly absorbed from the gut; peak plasma concentrations occurred within 30 min and were approximately 60% of equivalent i.v. doses. The distribution of BAU between plasma and most major organs was rapid and efficient, the exceptions being spleen and brain, which maintained only 40% and 10%, respectively, of the plasma BAU concentration. Approximately 41% of the injected dose of BAU was recovered intact in urine within 24 hr. Another 27% appeared as a more polar metabolite which, at a concentration of 50 microM, did not inhibit murine Urd phosphorylase. A near linear relationship was observed between the injected dose of BAU and its ability to increase the plasma concentration of Urd; i.v. injections of 30, 120 and 240 mg/kg increased plasma Urd 3-, 7- and 15-fold respectively. The utility of these data in the design of combination chemotherapy regimens containing BAU and related compounds is discussed.