Hepatic metabolism of MK-0457, a potent aurora kinase inhibitor: interspecies comparison and role of human cytochrome P450 and flavin-containing monooxygenase.
MK-0457 (N-[4([4-(4-methylpiperazin-1-yl)-6-[(3-methyl-1H-pyrazol-5 -yl)amino]pyrimidin-2-yl]thio)phenyl]cyclopropanecarboxamide), 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 cytochromes P450 and flavin-containing monoogygenases (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, whereas CYP3A4 only made a minor contribution. However, significant substrate inhibition was observed with MK-0457 N-demethylation at high substrate concentrations (>10 microM) in human liver microsomes relative to the anticipated therapeutic exposure. A multienzyme metabolic pathway such as this may mitigate the potential of drug interactions in clinical treatment with MK-0457.
Ballard
J E
JE
Department of Drug Metabolism, WP75A-203, Merck Research Laboratories, West Point, PA 19486, USA. jeanine_ballard@merck.com
Prueksaritanont
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T
Tang
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C
D000465:Algorithms; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D064127:Aurora Kinases; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004285:Dogs; D004791:Enzyme Inhibitors / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008252:Macaca fascicularis; D008995:Monoamine Oxidase / Q000378:metabolism*; D010879:Piperazines / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D013045:Species Specificity; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
D019138:Antibodies, Blocking; D064127:Aurora Kinases; D003577:Cytochrome P-450 Enzyme System; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D008995:Monoamine Oxidase; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; D011994:Recombinant Proteins; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines