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

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.104.002832v1 33/6/853    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 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 Zhao, P. Articles by Lee, C. A. Search for Related Content PubMed PubMed Citation Articles by Zhao, P. Articles by Lee, C. A.

EVALUATION OF TIME-DEPENDENT INACTIVATION OF CYP3A IN CRYOPRESERVED HUMAN HEPATOCYTES

Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development La Jolla Laboratories, San Diego, California (P.Z., C.A.L.); and Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, Washington (K.L.K.)

Irreversible CYP3A inhibition by drugs constitutes one of the major causes of inhibition-based drug interactions. We evaluated time-dependent inactivation of CYP3A in cryopreserved human hepatocytes for six structurally diverse compounds known to exhibit this property. Inactivation kinetic parameters were also determined using human liver microsomes. Except for diclofenac, which did not cause CYP3A inactivation either in microsomes or in hepatocytes at concentrations up to 100 µM, time-dependent inactivation was observed in hepatocytes for amprenavir, diltiazem, erythromycin, raloxifene, and troleandomycin. The observed inactivation potency in hepatocytes (observed IC₅₀) was compared with the potency predicted using microsomal parameters (predicted IC₅₀). Despite satisfactory prediction for troleandomycin (1.35 and 2.14 µM for the predicted and observed IC₅₀, respectively), over-prediction of inactivation was observed for raloxifene, amprenavir, and erythromycin (observed IC₅₀ values 6.2-, 55-, and 7.8-fold higher, respectively, than the predicted IC₅₀). By contrast, the observed IC₅₀ for diltiazem in hepatocytes was approximately 4-fold lower than the IC₅₀ predicted from microsomal data (under-prediction). After correcting for factors including nonspecific binding and inactivator consumption, prediction was significantly improved for raloxifene (the observed IC₅₀ then became 2-fold higher than the predicted IC₅₀) and for amprenavir to a lesser extent. A specific P-glycoprotein inhibitor, 4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-N-[2-(3.4-dimethoxyphenyl)ethyl]-6,7-dimethoxyquinazolin-2-amine (CP-100356), modulated the observed CYP3A inactivation potency by erythromycin and troleandomycin. In summary, these studies reveal three important factors that must be considered when microsomal inactivation parameters are used to predict inhibition-based drug interactions in intact cell systems.

This article has been cited by other articles:

				M. Kozawa, M. Honma, and H. Suzuki Quantitative Prediction of in Vivo Profiles of CYP3A4 Induction in Humans from in Vitro Results with a Reporter Gene Assay Drug Metab. Dispos., June 1, 2009; 37(6): 1234 - 1241. [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]

				K. Grime, P. J. H. Webborn, and R. J. Riley Functional Consequences of Active Hepatic Uptake on Cytochrome P450 Inhibition in Rat and Human Hepatocytes Drug Metab. Dispos., August 1, 2008; 36(8): 1670 - 1678. [Abstract] [Full Text] [PDF]

				A. Watanabe, K. Nakamura, N. Okudaira, O. Okazaki, and K.-i. Sudo Risk Assessment for Drug-Drug Interaction Caused by Metabolism-Based Inhibition of CYP3A Using Automated in Vitro Assay Systems and Its Application in the Early Drug Discovery Process Drug Metab. Dispos., July 1, 2007; 35(7): 1232 - 1238. [Abstract] [Full Text] [PDF]

				M. G. Soars, K. Grime, J. L. Sproston, P. J. H. Webborn, and R. J. Riley Use of Hepatocytes to Assess the Contribution of Hepatic Uptake to Clearance in Vivo Drug Metab. Dispos., June 1, 2007; 35(6): 859 - 865. [Abstract] [Full Text] [PDF]

				P. Zhao, C. A. Lee, and K. L. Kunze Sequential Metabolism Is Responsible for Diltiazem-Induced Time-Dependent Loss of CYP3A Drug Metab. Dispos., May 1, 2007; 35(5): 704 - 712. [Abstract] [Full Text] [PDF]

				D. F. McGinnity, A. J. Berry, J. R. Kenny, K. Grime, and R. J. Riley EVALUATION OF TIME-DEPENDENT CYTOCHROME P450 INHIBITION USING CULTURED HUMAN HEPATOCYTES Drug Metab. Dispos., August 1, 2006; 34(8): 1291 - 1300. [Abstract] [Full Text] [PDF]

				D. F. McGinnity, J. Tucker, S. Trigg, and R. J. Riley PREDICTION OF CYP2C9-MEDIATED DRUG-DRUG INTERACTIONS: A COMPARISON USING DATA FROM RECOMBINANT ENZYMES AND HUMAN HEPATOCYTES Drug Metab. Dispos., November 1, 2005; 33(11): 1700 - 1707. [Abstract] [Full Text] [PDF]