Received for publication March 9, 2007.
Revised May 22, 2007.
Accepted for publication May 23, 2007.

Hepatic metabolism of MK-0457, a potent Aurora kinase inhibitor: Interspecies comparison and role of human cytochrome P450 and flavin-containing monooxygenase

Abstract

MK-0457, an Aurora kinase inhibitor in development for the treatment of cancer, was evaluated for its in vitro metabolism in different species. This compound primarily underwent N-oxidation and N-demethylation in human, monkey, dog, and rat liver preparations. However, N-demethylation was less significant in dogs. The formation of minor metabolites varied with species, but all metabolites generated in human hepatocytes were observed in animals. Results of immunoinhibition, selective chemical inhibition, thermal inactivation and metabolism by recombinant CYPs and FMOs strongly suggest that CYP3A4 and FMO3 comparably contributed to MK-0457 N-oxidation in human liver microsomes, where the reaction conformed to Michaelis-Menten kinetics. These studies indicate a major role of CYP2C8 in the N-demethylation reaction, while CYP3A4 only made a minor contribution. However, significant substrate inhibition was observed with MK-0457 N-demethylation, at high substrate concentrations (>10 µM) in human liver microsomes relative to the anticipated therapeutic exposure. A multi-enzyme metabolic pathway such as this may mitigate the potential of drug interactions in clinical treatment with MK-0457.

Key words: CYP2C, CYP3A, cytochrome P450, drug development, enzyme kinetics, flavin-containing monooxygenase, hepatocytes, liver microsomes, metabolite identification