Pharmacokinetic model of R-roscovitine and its metabolite in healthy male subjects

OBJECTIVE: To characterize the pharmacokinetics of R-roscovitine, a novel cyclin-dependent kinase inhibitor, and its carboxylate metabolite in man. METHOD: Twelve healthy male subjects received single oral doses of 50, 100, 200, 400 or 800 mg in a hierarchical 3-period, 6-sequence crossover design. One dose was given after breakfast, the others under fasting conditions. R-roscovitine and the carboxylate metabolite were measured in plasma and urine. A 2-compartment model for R-roscovitine with 1 compartment for the metabolite and a component for first-pass extraction was adequate. Protein binding was calculated from plasma and urine data. RESULTS: R-roscovitine undergoes nonsaturatable first-pass extraction, rapid metabolism, exhibits high nonsaturated protein binding, is slowly absorbed from the GI tract and is rapidly and extensively distributed into tissues. The slow release of the molecule from tissue determines the apparent terminal half-life. Food delays the absorption and slows down the absorption rate but does not influence bioavailability. The formation rate of the carboxylate is a determinant of the plasma concentrations of this metabolite. It has low protein binding, limited tissue distribution and a renal clearance reflecting with good water solubility. CONCLUSION: The compartmental analysis clarified important pharmacokinetic aspects relevant for the clinical development of the compound.