A phenotype-genotype approach to predicting CYP450 and P-glycoprotein drug interactions with the mixed inhibitor/inducer tipranavir/ritonavir.
Article Details
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Dumond JB, Vourvahis M, Rezk NL, Patterson KB, Tien HC, White N, Jennings SH, Choi SO, Li J, Wagner MJ, La-Beck NM, Drulak M, Sabo JP, Castles MA, Macgregor TR, Kashuba AD
A phenotype-genotype approach to predicting CYP450 and P-glycoprotein drug interactions with the mixed inhibitor/inducer tipranavir/ritonavir.
Clin Pharmacol Ther. 2010 Jun;87(6):735-42. doi: 10.1038/clpt.2009.253. Epub 2010 Feb 10.
- PubMed ID
- 20147896 [ View in PubMed]
- 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-infinity) 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.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Tipranavir Cytochrome P450 2C19 Protein Humans UnknownSubstrateInhibitorDetails Tipranavir Cytochrome P450 2D6 Protein Humans UnknownSubstrateInhibitorDetails Tipranavir Cytochrome P450 3A4 Protein Humans UnknownSubstrateInhibitorDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareEsomeprazoleTipranavir The metabolism of Esomeprazole can be increased when combined with Tipranavir. FlecainideTipranavir The serum concentration of Flecainide can be increased when it is combined with Tipranavir. ItraconazoleTipranavir The metabolism of Itraconazole can be increased when combined with Tipranavir. OmeprazoleTipranavir The metabolism of Omeprazole can be increased when combined with Tipranavir.