Use of Immortalized Human Hepatocytes to Predict the Magnitude of Clinical Drug-Drug Interactions Caused by CYP3A4 Induction
Autor: | Jennifer L. Liras, Sonia M. de Morais, Jessica B. Mills, Odette A. Fahmi, Sharon L. Ripp, Tristan S. Maurer, Kristen A. Trevena |
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Rok vydání: | 2006 |
Předmět: |
Nifedipine
Cell Survival Pharmaceutical Science Pharmacology Dexamethasone Cell Line Rosiglitazone Cytochrome P-450 Enzyme System In vivo Cytochrome P-450 CYP3A medicine Humans Drug Interactions Cell Proliferation Dose-Response Relationship Drug Pioglitazone biology CYP3A4 Reproducibility of Results Cytochrome P450 Drug interaction Sulfinpyrazone In vitro Dose–response relationship Carbamazepine medicine.anatomical_structure Enzyme Induction Phenobarbital Phenytoin Hepatocyte Immunology Hepatocytes biology.protein Thiazolidinediones Rifampin Algorithms |
Zdroj: | Drug Metabolism and Disposition. 34:1742-1748 |
ISSN: | 1521-009X 0090-9556 |
Popis: | Cytochrome P4503A4 (CYP3A4) is the principal drug-metabolizing enzyme in human liver. Drug-drug interactions (DDIs) caused by induction of CYP3A4 can result in decreased exposure to coadministered drugs, with potential loss of efficacy. Immortalized hepatocytes (Fa2N-4 cells) have been proposed as a tool to identify CYP3A4 inducers. The purpose of the current studies was to characterize the effect of known inducers on CYP3A4 in Fa2N-4 cells, and to determine whether these in vitro data could reliably project the magnitude of DDIs caused by induction. Twenty-four compounds were chosen for these studies, based on previously published data using primary human hepatocytes. Eighteen compounds had been shown to be positive for induction, and six compounds had been shown to be negative for induction. In Fa2N-4 cells, all 18 positive controls produced greater than 2-fold maximal CYP3A4 induction, and all 6 negative controls produced less than 1.5-fold maximal CYP3A4 induction. Subsequent studies were conducted to determine the relationship between in vitro induction data and in vivo induction response. The approach was to relate in vitro induction data (E(max) and EC(50) values) with efficacious free plasma concentrations to calculate a relative induction score. This score was then correlated with decreases in area under the plasma concentration versus time curve values for coadministered CYP3A4 object drugs (midazolam or ethinylestradiol) from previously published clinical DDI studies. Excellent correlations (r(2) values >0.92) were obtained, suggesting that Fa2N-4 cells can be used for identification of inducers as well as prediction of the magnitude of clinical DDIs. |
Databáze: | OpenAIRE |
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