Abstract
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.
Footnotes
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This work was supported in part by Ministry of Education of Czech Republic (project MSM6198959216); Grant Agency of Czech Republic [Grants 301/08/1649, 303/09/H048]; and Palacky University [Grant 91110221] (internal grant).
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.108.025502.
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ABBREVIATIONS: P450, cytochrome P450; CDK, cyclin-dependent kinase; HPLC, high-liquid performance chromatography; ESI, electrospray ionization; MS/MS, tandem mass spectroscopy; MS, mass spectrometry.
- Received November 4, 2008.
- Accepted February 26, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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