Comparative studies to determine the selective inhibitors for P-glycoprotein and cytochrome P 4503A4
| Autor: | Kiyomi Ito, Yuichi Sugiyama, Meguru Achira, Hiroshi Suzuki |
|---|---|
| Rok vydání: | 1999 |
| Předmět: |
Cytochrome
Midazolam Pharmaceutical Science Cyclosporins Pharmacology Vinblastine Piperazines Article Mixed Function Oxygenases Cytochrome P-450 Enzyme System Microsomes Intestine Small Cytochrome P-450 CYP3A medicine Cytochrome P-450 Enzyme Inhibitors Humans ATP Binding Cassette Transporter Subfamily B Member 1 Enzyme Inhibitors P-glycoprotein biology CYP3A4 Chemistry Ketoconazole Liver Verapamil Indans biology.protein Microsome Caco-2 Cells medicine.drug |
| Zdroj: | AAPS PharmSci. 1:14-19 |
| ISSN: | 1522-1059 |
| Popis: | It has been suggested that cytochrome P450 3A4 (CYP3A4) and MDR1 P-glycoprotein (P-gp) act synergistically to limit the bioavailability of orally administered agents. In order to determine the relative role of these proteins, it is essential to identify a selective inhibitor for either P-gp or CYP3A4. In the present investigation, comparative studies were performed to examine the effect of inhibitors on the function of these proteins. The IC50 of P-gp function, determined by examining the inhibition of the transcellular transport of vinblastine across Caco-2 monolayers, was in the order PSC833 ≪ ketoconazole, verapamil ≪ N-(2(R)-hydroxy-1(S)-indanyl)-5-(2(S)-(1,1-dimethylethylaminocarbonyl)-4-(furo(2,3-b)pyridin-5-yl) methyl)piperazin-1-yl)-4(S)-hydroxy-2(R)-phenylmethylpentanamide (L-754,394). In contrast, the IC50 of CYP3A4 function, determined by examining the inhibition of the metabolism of midazolam by intestinal and liver microsomes, was in the order L-754,384 ≪ketoconazole≪ PSC 833 and verapamil. The ratio of IC50 for P-gp to that for CYP3A4 was more than 200 for L-754,394,60 ∼ 150 for ketoconazole, 1.5 for verapamil, and 0.05 for PSC 833. Collectively, it was demonstrated that PSC 833 and L-754,394 can be used as selective inhibitors of P-gp and CYP3A4, respectively. |
| Databáze: | OpenAIRE |
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