Metabolism of the trisubstituted purine cyclin-dependent kinase inhibitor seliciclib (R-roscovitine) in vitro and in vivo.

Seliciclib (R-roscovitine, CYC202) is a small molecule inhibitor of cyclin-dependent kinases currently in phase II clinical trials as an anticancer agent. We examined the metabolism of seliciclib in vitro and in vivo. Using radiolabeled seliciclib we found that cytochrome P450 (P450)-mediated metabolism in liver microsomes from human, rat, mouse, rabbit, monkey, and dog was rapid to a number of metabolic species, one of the most prevalent being a carboxylate previously identified in urine from rats and mice dosed with seliciclib. Metabolism was fastest in mouse microsomes and slowest in microsomes from dog. Using characterized human microsomes, we identified the P450s responsible for this metabolism as CYP3A4 and CYP2B6. Glucuronidation of seliciclib and its metabolites was shown to be a major elimination process in bile duct-cannulated rats dosed with [(14)C]seliciclib at 10 mg/kg. Elimination by the fecal route accounted for up to 65% of the administered dose, whereas urinary excretion accounted for up to 43%. Almost half of the administered dose was found to be eliminated via the bile, and elimination was found to be rapid, with up to 88% of the dose being excreted within the first 24 h. Preliminary experiments indicated that UDP-glucuronosyltransferase (UGT) 1A3, 1A9, and 2B7 were involved in the conjugation of seliciclib. Seliciclib was further shown in vitro to inhibit the activity of some of the enzymes responsible for its metabolism. Cytochrome P450s CYP3A4 and CYP2C9 and UGT1A1 were all inhibited at concentrations achieved in human trials, which raises the possibility of drug-drug interactions in the clinic.