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Pharmacokinetics and Metabolism of Cyclopentenyl Cytosine in Nonhuman Primates

Walter Reed Army Medical Center, Washington, DC 20307 [S. M. B.], and The Pediatric Branch [F. M. B., R. L. H., C. M., R. F. M., D. G. P.] and the Laboratory of Medicinal Chemistry [L. H., J. A. K.], National Cancer Institute, Bethesda, Maryland 20892

The plasma and cerebrospinal fluid pharmacokinetics of cyclopentenyl cytosine (CPE-C) were studied following i.v. bolus and continuous i.v. infusion in male rhesus monkeys. Following an i.v. bolus dose of 100 mg/m² plasma elimination of CPE-C was biexponential with a mean t of 8.4 min, a mean tß of 36 min, and a total clearance (CL_TB) of 662 ml/min/m², which is 5- to 10-fold higher than clearance rates in rodents and dogs. Less than 20% of the total dose of CPE-C was excreted unchanged in the urine. The remainder was excreted as the inactive deamination product cyclopentenyl uridine (CPE-U). The ratio of the areas under the plasma concentration versus time curves of CPE-U to CPE-C was 7.0 ± 2.4 following i.v. bolus CPE-C. The cerebrospinal fluid:plasma ratios of CPE-C and CPE-U were 0.08 and 0.30, respectively. Continuous i.v. infusion of CPE-C was compared to continuous infusion of 1-ß-D-arabinofuranosylcytosine in two monkeys. Steady state plasma concentrations, normalized to a dose of 12.5 mg/m²/h of CPE-C and an equimolar dose of 1-ß-D-arabinofuranosylcytosine, were 2.1 and 0.53 µM, respectively. The steady state concentrations of their corresponding uridine metabolites (CPE-U and 1-ß-D-arabinofuranosyluridine) were 8.2 and 15.5 µM. The rapid elimination of CPE-C by deamination in the primate resulted in a much higher CL_TB and considerably lower total drug exposure than in rodents and dogs that clear CPE-C at a much lower rate by renal excretion. These significant interspecies differences in the disposition of CPE-C should be considered in the selection of a starting dose and schedule for human trials and suggest that a pharmacologically directed dose escalation scheme should be used in the planned phase I studies.

¹ To whom requests for reprints should be addressed, at the Pediatric Branch, National Cancer Institute, Building 10, Room 13N240, 9000 Rockville Pike, Bethesda, MD 20892.

Received 6/15/90. Accepted 9/17/90.