A Phenotype–Genotype Approach to Predicting CYP450 and P-Glycoprotein Drug Interactions With the Mixed Inhibitor/Inducer Tipranavir/Ritonavir
- 10 February 2010
- journal article
- research article
- Published by Wiley in Clinical Pharmacology & Therapeutics
- Vol. 87 (6), 735-742
- https://doi.org/10.1038/clpt.2009.253
Abstract
The effects of tipranavir/ritonavir (TPV/r) on hepatic and intestinal P‐glycoprotein (P‐gp) and cytochrome P450 (CYP) enzyme activity were evaluated in 23 volunteers. The subjects received oral (p.o.) caffeine, warfarin + vitamin K, omeprazole, dextromethorphan, and midazolam and digoxin (p.o. and intravenous (i.v.)) at baseline, during the first three doses of TPV/r (500 mg/200 mg b.i.d.), and at steady state. Plasma area under the curve (AUC)0–∞ and urinary metabolite ratios were used for quantification of protein activities. A single dose of TPV/r had no effect on the activity of CYP1A2 and CYP2C9; it weakly inhibited CYP2C19 and P‐gp; and it potently inhibited CYP2D6 and CYP3A. Multiple dosing produced weak induction of CYP1A2, moderate induction of CYP2C19, potent induction of intestinal P‐gp, and potent inhibition of CYP2D6 and CYP3A, with no significant effects on CYP2C9 and hepatic P‐gp. Several P450/transporter single‐nucleotide polymorphisms correlated with the baseline phenotype but not with the extent of inhibition or induction. Although mixed induction and inhibition are present, this approach offers an understanding of drug interaction mechanisms and ultimately assists in optimizing the clinical use of TPV/r. Clinical Pharmacology & Therapeutics (2010) 87 6, 735–742. doi: 10.1038/clpt.2009.253Keywords
This publication has 19 references indexed in Scilit:
- Relative Impact of Genotype and Enzyme Induction on the Metabolic Capacity of CYP2C9 in Healthy VolunteersClinical Pharmacology & Therapeutics, 2009
- In vitro and in vivo assessment of the effect of dalcetrapib on a panel of CYP substratesCurrent Medical Research and Opinion, 2009
- Pharmacokinetics, Safety, and Efficacy of Tipranavir Boosted With Ritonavir Alone or in Combination With Other Boosted Protease Inhibitors as Part of Optimized Combination Antiretroviral Therapy in Highly Treatment-Experienced Patients (BI Study 1182.51)JAIDS Journal of Acquired Immune Deficiency Syndromes, 2008
- Interaction between lopinavir/ritonavir and warfarinCMAJ : Canadian Medical Association Journal, 2007
- Gene and Protein Expression of P-Glycoprotein, MRP1, MRP2, and CYP3A4 in the Small and Large Human IntestineMolecular Pharmaceutics, 2007
- Coadministration of Lopinavir/Ritonavir and Phenytoin Results in Two-Way Drug Interaction Through Cytochrome P-450 InductionJAIDS Journal of Acquired Immune Deficiency Syndromes, 2004
- Substantial pharmacokinetic interaction between digoxin and ritonavir in healthy volunteers*1Clinical Pharmacology & Therapeutics, 2004
- Combined phenotypic assessment of cytochrome P450 1A2, 2C9, 2C19, 2D6, and 3A, N-acetyltransferase-2, and xanthine oxidase activities with the “Cooperstown 5+1 cocktail”Clinical Pharmacology & Therapeutics, 2003
- Determination of Urinary Metabolites of Caffeine for the Assessment of Cytochrome P4501A2, Xanthine Oxidase, and N-Acetyltransferase Activity in HumansTherapeutic Drug Monitoring, 1996
- Variability in caffeine metabolismClinical Pharmacology & Therapeutics, 1983