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Drug Metabolism and Disposition Fast Forward
First published on February 27, 2009; DOI: 10.1124/dmd.108.025502

0090-9556/09/3706-1198-1202$20.00
DMD 37:1198-1202, 2009

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Interactions of Olomoucine II with Human Liver Microsomal Cytochromes P450

Michal Siller, Pavel Anzenbacher, Eva Anzenbacherova, Karel Dolezal, Igor Popa, and Miroslav Strnad

Departments of Pharmacology (M.S., P.A.) and Medicinal Chemistry and Biochemistry (E.A.), Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic; Laboratory of Growth Regulators, Palacky University and Institute of Experimental Botany, Academy of Science, Olomouc, Czech Republic (K.D., I.P., M.S.); and Department of Inorganic Chemistry, Faculty of Science, Palacky University, Olomouc, Czech Republic (I.P.)

Olomoucine II is a cyclin-dependent kinase inhibitor and a potential antineoplastic agent because it can arrest animal cell cycles. This study examines its interactions with human liver microsomal cytochrome P450 (P450) enzymes. Spectroscopic and high-performance liquid chromatography (HPLC) methods were used to estimate the degree of olomoucine II-mediated inhibition of enzymatic activities of eight drug-metabolizing P450s in vitro. In addition, mass spectrometry coupled with HPLC was used to identify an olomoucine II metabolite (2,5-dihydroxyroscovitine) formed in the reaction mixtures, and CYP3A4 was found to be responsible for the hydroxylation of the N6-benzyl ring at position 5, leading to this compound. Olomoucine II significantly inhibited the enzymatic activities of CYP1A2, CYP2C9, and (to a lesser degree) CYP3A4. The results indicate that use of olomoucine II as a drug could affect the activities of CYP3A4, CYP1A2, and CYP2C9 in vivo. Hence, the clinical relevance of these interactions should be carefully evaluated.

Address correspondence to: Michal Siller, Palacky University at Olomouc, Faculty of Medicine, and Dentistry, Department of Pharmacology, Hnevotínská3, 775 15 Olomouc, Czech Republic. E-mail: michal.siller{at}seznam.cz






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