Preclinical pharmacokinetics of β-L-dioxolane-cytidine, a novel anticancer agent, in rats

Abstract

 Purpose: β-L-Dioxolane-cytidine (OddC), a novel L-nucleoside analog with potent cytotoxicity in vitro, appears to be a promising candidate for anticancer therapy. In this study, a high performance liquid chromatography (HPLC) analytical method was developed and the preclinical pharmacokinetics of OddC were characterized in rats. Methods: Adult male Sprague Dawley rats were given 10, 25, or 50 mg/kg of OddC both intravenously and orally with a 6-day washout period between doses. Each rat received one dosage level of OddC and the route of administration was assessed by a randomized crossover design. Plasma and urine concentrations were determined by HPLC. Pharmacokinetic parameters were generated by area-moment analysis. Results: Following intravenous administration, the plasma concentrations of OddC declined rapidly in a biexponential manner with a terminal phase half-life of 1.65±1.12 h (mean±SD). Mean total, renal, and nonrenal clearances were 1.38±0.62, 0.30±0.14, and 1.08±0.59 l/h per kg. Approximately 22% of the administered dose was excreted unchanged in the urine. Thus, nonrenal clearance was the predominant route of elimination of OddC. The steady-state volume of distribution averaged 1.42±0.66 l/kg, indicating intracellular distribution of OddC. The nucleoside analog was slowly absorbed after oral administration and bioavailability varied greatly between individual rats, averaging 41±27% when calculated from urinary excretion data and 37±25% when calculated from plasma OddC concentration data. Conclusion: The pharmacokinetics of OddC in rats were linear over the dose range studied.