TY - JOUR T1 - Interactions of Olomoucine II with Human Liver Microsomal Cytochromes P450 JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1198 LP - 1202 DO - 10.1124/dmd.108.025502 VL - 37 IS - 6 AU - Michal Siller AU - Pavel Anzenbacher AU - Eva Anzenbacherova AU - Karel Dolezal AU - Igor Popa AU - Miroslav Strnad Y1 - 2009/06/01 UR - http://dmd.aspetjournals.org/content/37/6/1198.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -