Potent cytochrome P450 2C19 genotype–related interaction between voriconazole and the cytochrome P450 3A4 inhibitor ritonavir
| Autor: | Magdalena Drzewinska, Johanna Weiss, Verena Schöwel, Reinhard Ding, Jürgen Burhenne, Jens Rengelshausen, Gerd Mikus, Klaus-Dieter Riedel, Walter E. Haefeli, T. Thomsen |
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| Rok vydání: | 2006 |
| Předmět: |
Adult
Male Antifungal Agents Genotype Anti-HIV Agents Pharmacology Mixed Function Oxygenases Double-Blind Method Pharmacokinetics medicine Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme Inhibitors Humans Pharmacology (medical) Enzyme Inhibitors Alleles Voriconazole Cross-Over Studies Ritonavir Dose-Response Relationship Drug CYP3A4 biology Chemistry Triazoles Crossover study Cytochrome P-450 CYP2C19 Dose–response relationship Pyrimidines Cytochrome P450 3A4 Inhibitor Enzyme inhibitor Area Under Curve biology.protein Female Aryl Hydrocarbon Hydroxylases medicine.drug |
| Zdroj: | Clinical Pharmacology & Therapeutics. 80:126-135 |
| ISSN: | 0009-9236 |
| DOI: | 10.1016/j.clpt.2006.04.004 |
| Popis: | Objectives Cytochrome P450 (CYP) 2C19 and CYP3A4 are the major enzymes responsible for voriconazole elimination. Because the activity of CYP2C19 is under genetic control, the extent of inhibition with a CYP3A4 inhibitor was expected to be modulated by the CYP2C19 metabolizer status. This study thus assessed the effect of the potent CYP3A4 inhibitor ritonavir after short-term administration on voriconazole pharmacokinetics in extensive metabolizers (EMs) and poor metabolizers (PMs) of CYP2C19. Methods In a randomized, placebo-controlled crossover study, 20 healthy participants who were stratified according to CYP2C19 genotype received oral ritonavir (300 mg twice daily) or placebo for 2 days. Together with the first ritonavir or placebo dose, a single oral dose of 400 mg voriconazole was administered. Voriconazole was determined in plasma and urine by liquid chromatography-mass spectrometry, and pharmacokinetic parameters were estimated by noncompartmental analysis. Results When given alone, the apparent oral clearance of voriconazole after single oral dosing was 26% ± 16% (P > .05) lower in CYP2C19*1/*2 individuals and 66% ± 14% (P < .01) lower in CYP2C19 PMs. The addition of ritonavir caused a major reduction in voriconazole apparent oral clearance (354 ± 173 mL/min versus 202 ± 139 mL/min, P = .0001). This reduction occurred in all CYP2C19 genotypes (463 ± 168 mL/min versus 305 ± 112 mL/min [P = .023] for *1/*1, 343 ± 127 mL/min versus 190 ± 93 mL/min [P = .008] for *1/*2, and 158 ± 54 mL/min versus 22 ± 11 mL/min for *2/*2) and is probably caused by inhibition of CYP3A4-mediated voriconazole metabolism. Conclusions Coadministration of a potent CYP3A4 inhibitor leads to a higher and prolonged exposure with voriconazole that might increase the risk of the development of adverse drug reactions on a short-term basis, particularly in CYP2C19 PM patients. Clinical Pharmacology & Therapeutics (2006) 80, 126–135; doi: 10.1016/j.clpt.2006.04.004 |
| Databáze: | OpenAIRE |
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