Evaluation of First-Pass Cytochrome P4503A (CYP3A) and P-Glycoprotein Activities Using Alfentanil and Fexofenadine in Combination
| Autor: | Evan D. Kharasch, Pamela Sheffels, Christine Hoffer, Alysa Walker |
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| Rok vydání: | 2005 |
| Předmět: |
Adult
Male CYP3A Pharmacology Cytochrome P-450 Enzyme System medicine Cytochrome P-450 CYP3A Humans Pharmacology (medical) ATP Binding Cassette Transporter Subfamily B Member 1 Alfentanil P-glycoprotein Meal Cross-Over Studies Fexofenadine biology Chemistry Crossover study Bioavailability Drug Combinations Anesthesia biology.protein Female Terfenadine Drug metabolism medicine.drug |
| Zdroj: | The Journal of Clinical Pharmacology. 45:79-88 |
| ISSN: | 0091-2700 |
| Popis: | Cytochrome P4503A (CYP3A) and P-glycoprotein (P-gp) are major determinants of oral bioavailability. Development of in vivo probe(s), for both CYP3A and P-gp, which could be administered in combination, is a current goal. Nevertheless, there is considerable overlap in CYP3A and P-gp substrate selectivities; there are few discrete probes. Alfentanil is a selective CYP3A probe but not a P-gp substrate. Fexofenadine is a P-gp probe but not a CYP3A substrate. This investigation tested the hypothesis that alfentanil and fexofenadine could be administered in combination to probe first-pass CYP3A and P-gp activities in humans. Two 3-way crossover studies were conducted in healthy volunteers. In the first protocol, subjects received oral alfentanil alone, fexofenadine alone, or fexofenadine 1 hour after alfentanil. In the second protocol, subjects abstained from citrus and apple products for 5 days and received fexofenadine alone, fexofenadine 1 hour after alfentanil, or alfentanil 4 hours after fexofenadine. An assay using solid-phase extraction and electrospray liquid chromatography/mass spectrometry was developed for the simultaneous quantification of plasma alfentanil and fexofenadine. In both protocols, alfentanil plasma concentrations and area under the concentration versus time curve (AUC) were unaffected by fexofenadine or meal composition. Fexofenadine given 1 hour after alfentanil and followed 1 hour later by a meal containing orange or apple juice had a somewhat lower AUC compared with fexofenadine alone (geometric mean ratio with and without the interacting drug = 0.73, 90% confidence interval [CI] = 0.59-1.04). Fexofenadine given 1 hour after alfentanil and followed 2 hours later by a meal not containing citrus or apple products had an AUC that was unchanged compared with fexofenadine alone (ratio = 0.91, 90% CI = 0.70-1.35). These results show that alfentanil disposition was not affected by fexofenadine. A dosing regimen was identified in which fexofenadine disposition was not affected by alfentanil. The timing and content of meals after fexofenadine had a significant effect on fexofenadine disposition. Alfentanil and fexofenadine in combination appear to be a useful probe for evaluating both first-pass CYP3A and P-gp activities in humans. |
| Databáze: | OpenAIRE |
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