Received for publication October 16, 2007.
Revised November 28, 2007.
Accepted for publication November 28, 2007.

METABOLISM OF THE TRISUBSTITUTED PURINE CYCLIN-DEPENDENT KINASE INHIBITOR SELICICLIB (R-ROSCOVITINE) IN VITRO AND IN VIVO

Abstract

Seliciclib (R-roscovitine, CYC202) is a small molecule inhibitor of cyclin-dependent kinases currently in Phase II clinical trials as an anti-cancer agent. We examined the metabolism of seliciclib in vitro and in vivo. Using radiolabelled seliciclib we found that cytochrome 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 characterised 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 [¹⁴C]-seliciclib at 10 mg/kg. Elimination by the faecal route accounted for up to 65% of the administered dose, while 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 hours. Preliminary experiments indicated that UGT1A3, 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 2C9 as well as UGT1A1 were all inhibited at concentrations achieved in human trials, which raises the possibility of drug-drug interactions in the clinic.

Key words: CYP inhibition, cytochrome P450, drug-drug interactions, enzyme inhibitors, glucuronidation, hepatobiliary disposition, phase II drug metabolism

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