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

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.105.006874v1 34/1/166    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 Galetin, A. Articles by Houston, J. B. Search for Related Content PubMed PubMed Citation Articles by Galetin, A. Articles by Houston, J. B.

PREDICTION OF TIME-DEPENDENT CYP3A4 DRUG-DRUG INTERACTIONS: IMPACT OF ENZYME DEGRADATION, PARALLEL ELIMINATION PATHWAYS, AND INTESTINAL INHIBITION

School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, United Kingdom

Time-dependent inhibition of CYP3A4 often results in clinically significant drug-drug interactions. In the current study, 37 in vivo cases of irreversible inhibition were collated, focusing on macrolides (erythromycin, clarithromycin, and azithromycin) and diltiazem as inhibitors. The interactions included 17 different CYP3A substrates showing up to a 7-fold increase in AUC (13.5% of studies were in the range of potent inhibition). A systematic analysis of the impact of CYP3A4 degradation half-life (mean t_1/2deg = 3 days, ranging from 1 to 6 days) on the prediction of the extent of interaction for compounds with a differential contribution from CYP3A4 to the overall elimination (defined by fm_CYP3A4) was performed. Although the prediction accuracy was very sensitive to the CYP3A4 degradation rate for substrates mainly eliminated by this enzyme (fm_CYP3A4 0.9), minimal effects are observed when CYP3A4 contributes less than 50% to the overall elimination in cases when the parallel elimination pathway is not subject to inhibition. Use of the mean CYP3A4 t_1/2deg (3 days), average unbound systemic plasma concentration of the inhibitor, and the corresponding fm_CYP3A4 resulted in 89% of studies predicted within 2-fold of the in vivo value. The impact of the interaction in the gut wall was assessed by assuming maximal intestinal inhibition of CYP3A4. Although a reduced number of false-negative predictions was observed, there was an increased number of overpredictions, and generally, a loss of prediction accuracy was observed. The impact of the possible interplay between CYP3A4 and efflux transporters on the intestinal interaction requires further evaluation.

This article has been cited by other articles:

				M. Shou, M. Hayashi, Y. Pan, Y. Xu, K. Morrissey, L. Xu, and G. L. Skiles Modeling, Prediction, and in Vitro in Vivo Correlation of CYP3A4 Induction Drug Metab. Dispos., November 1, 2008; 36(11): 2355 - 2370. [Abstract] [Full Text] [PDF]

				C. Lu, P. Hatsis, C. Berg, F. W. Lee, and S. K. Balani Prediction of Pharmacokinetic Drug-Drug Interactions Using Human Hepatocyte Suspension in Plasma and Cytochrome P450 Phenotypic Data. II. In Vitro-in Vivo Correlation with Ketoconazole Drug Metab. Dispos., July 1, 2008; 36(7): 1255 - 1260. [Abstract] [Full Text] [PDF]

				C. Lu, C. Berg, S. R. Prakash, F. W. Lee, and S. K. Balani Prediction of Pharmacokinetic Drug-Drug Interactions Using Human Hepatocyte Suspension in Plasma and Cytochrome P450 Phenotypic Data. III. In Vitro-in Vivo Correlation with Fluconazole Drug Metab. Dispos., July 1, 2008; 36(7): 1261 - 1266. [Abstract] [Full Text] [PDF]

				M. Gertz, P. J. Kilford, J. B. Houston, and A. Galetin Drug Lipophilicity and Microsomal Protein Concentration as Determinants in the Prediction of the Fraction Unbound in Microsomal Incubations Drug Metab. Dispos., March 1, 2008; 36(3): 535 - 542. [Abstract] [Full Text] [PDF]

				A. Ogasawara, T. Kume, and E. Kazama Effect of Oral Ketoconazole on Intestinal First-Pass Effect of Midazolam and Fexofenadine in Cynomolgus Monkeys Drug Metab. Dispos., March 1, 2007; 35(3): 410 - 418. [Abstract] [Full Text] [PDF]

				R. S. Obach, R. L. Walsky, and K. Venkatakrishnan Mechanism-Based Inactivation of Human Cytochrome P450 Enzymes and the Prediction of Drug-Drug Interactions Drug Metab. Dispos., February 1, 2007; 35(2): 246 - 255. [Abstract] [Full Text] [PDF]

				C. Lu, G. T. Miwa, S. R. Prakash, L.-S. Gan, and S. K. Balani A Novel Model for the Prediction of Drug-Drug Interactions in Humans Based on in Vitro Cytochrome P450 Phenotypic Data Drug Metab. Dispos., January 1, 2007; 35(1): 79 - 85. [Abstract] [Full Text] [PDF]