QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.106.118471v1 321/2/553    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dennison, J. B. Articles by Hall, S. D. Search for Related Content PubMed PubMed Citation Articles by Dennison, J. B. Articles by Hall, S. D.

METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Effect of CYP3A5 Expression on Vincristine Metabolism with Human Liver Microsomes

Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana

Vincristine is preferentially metabolized to a secondary amine, M1, by CYP3A5 with a 9- to 14-fold higher intrinsic clearance than CYP3A4 using cDNA-expressed enzymes. The genetically polymorphic expression of CYP3A5 may contribute to interindividual variability in vincristine efficacy and toxicity. The current study quantifies the contribution of cytochromes P450 (P450s), including CYP3A4 and CYP3A5, to vincristine metabolism with a bank of human liver microsomes (HLMs). M1 was the major metabolite formed with HLMs, and selective chemical inhibition of P450s confirmed that CYP3A was the major metabolizing subfamily. The liver tissues were genotyped for low expression alleles, CYP3A5*3,*6, and *7, and the HLMs were phenotyped for CYP3A4 and CYP3A5 expression by Western blot. Testosterone 6-hydroxylation and itraconazole hydroxylation were used to quantify CYP3A4 activity in the HLMs. For each CYP3A5 high expresser (n = 10), the rate of M1 formation from vincristine due to CYP3A5 was quantified by subtracting the CYP3A4 contribution as determined by linear regression with CYP3A5*3/*3 samples. For CYP3A5 high expressers, the contribution of CYP3A5 to the metabolism of vincristine was 54 to 95% of the total activity, and the rate of M1 formation mediated by CYP3A5 correlated with CYP3A5 protein content (r² = 0.95). Selective inhibition of CYP3A4 demonstrated that the M1 formation rate with CYP3A5 high expressers was differentially inhibited based on CYP3A4 activity. Using median values, the estimated hepatic clearances were 5-fold higher for CYP3A5 high expressers than low expressers. We conclude that polymorphic expression of CYP3A5 may be a major determinant in the P450-mediated clearance of vincristine.

Address correspondence to: Dr. Stephen D. Hall, Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, 1001 West 10th St., W7123, Indianapolis, IN 46202. E-mail: sdhall{at}iupui.edu

This article has been cited by other articles:

				Y. Okada, N. Murayama, C. Yanagida, M. Shimizu, F. P. Guengerich, and H. Yamazaki Drug Interactions of Thalidomide with Midazolam and Cyclosporine A: Heterotropic Cooperativity of Human Cytochrome P450 3A5 Drug Metab. Dispos., January 1, 2009; 37(1): 18 - 23. [Abstract] [Full Text] [PDF]

				X. Zhang, D. R. Jones, and S. D. Hall Prediction of the Effect of Erythromycin, Diltiazem, and Their Metabolites, Alone and in Combination, on CYP3A4 Inhibition Drug Metab. Dispos., January 1, 2009; 37(1): 150 - 160. [Abstract] [Full Text] [PDF]

				J. M. Fujitaki, E. E. Cable, B. R. Ito, B.-H. Zhang, J. Hou, C. Yang, D. A. Bullough, J. L. Ferrero, P. D. van Poelje, D. L. Linemeyer, et al. Preclinical Pharmacokinetics of a HepDirect Prodrug of a Novel Phosphonate-Containing Thyroid Hormone Receptor Agonist Drug Metab. Dispos., November 1, 2008; 36(11): 2393 - 2403. [Abstract] [Full Text] [PDF]

				J. B. Dennison, M. A. Mohutsky, R. J. Barbuch, S. A. Wrighton, and S. D. Hall Apparent High CYP3A5 Expression Is Required for Significant Metabolism of Vincristine by Human Cryopreserved Hepatocytes J. Pharmacol. Exp. Ther., October 1, 2008; 327(1): 248 - 257. [Abstract] [Full Text] [PDF]

				H.-Y. Ku, H.-J. Ahn, K.-A. Seo, H. Kim, M. Oh, S. K. Bae, J.-G. Shin, J.-H. Shon, and K.-H. Liu The Contributions of Cytochromes P450 3A4 and 3A5 to the Metabolism of the Phosphodiesterase Type 5 Inhibitors Sildenafil, Udenafil, and Vardenafil Drug Metab. Dispos., June 1, 2008; 36(6): 986 - 990. [Abstract] [Full Text] [PDF]

				S. K. Quinney, R. E. Galinsky, V. A. Jiyamapa-Serna, Y. Chen, M. A. Hamman, S. D. Hall, and R. E. Kimura Hydroxyitraconazole, Formed During Intestinal First-Pass Metabolism of Itraconazole, Controls the Time Course of Hepatic CYP3A Inhibition and the Bioavailability of Itraconazole in Rats Drug Metab. Dispos., June 1, 2008; 36(6): 1097 - 1101. [Abstract] [Full Text] [PDF]

				N. Isoherranen, S. R. Ludington, R. C. Givens, J. K. Lamba, S. N. Pusek, E. C. Dees, D. K. Blough, K. Iwanaga, R. L. Hawke, E. G. Schuetz, et al. The Influence of CYP3A5 Expression on the Extent of Hepatic CYP3A Inhibition Is Substrate-Dependent: An in Vitro-in Vivo Evaluation Drug Metab. Dispos., January 1, 2008; 36(1): 146 - 154. [Abstract] [Full Text] [PDF]