Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2010 Jun;87(6):735-42.
doi: 10.1038/clpt.2009.253. Epub 2010 Feb 10.

A phenotype-genotype approach to predicting CYP450 and P-glycoprotein drug interactions with the mixed inhibitor/inducer tipranavir/ritonavir

J B Dumond  1 , M Vourvahis, N L Rezk, K B Patterson, H-C Tien, N White, S H Jennings, S O Choi, J Li, M J Wagner, N M La-Beck, M Drulak, J P Sabo, M A Castles, T R Macgregor, A D M Kashuba
Affiliations
Randomized Controlled Trial

A phenotype-genotype approach to predicting CYP450 and P-glycoprotein drug interactions with the mixed inhibitor/inducer tipranavir/ritonavir

J B Dumond et al. Clin Pharmacol Ther. 2010 Jun.

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.

PubMed Disclaimer

Conflict of interest statement

CONFLICT OF INTEREST

M.D., J.P.S., M.A.C., and T.R.M. are employed by Boehringer Ingelheim Pharmaceuticals, Inc. The other authors declared no conflict of interest.

Figures

Figure 1
Figure 1
Concentration–time curve at baseline, after first dose, and at steady state of (a) caffeine (CYP1A2), (b) S-warfarin (CYP2C9), (c) omeprazole (CYP2C19), (d) dextromethorphan (CYP2D6), (e) i.v. midazolam (hepatic CYP3A), (f) p.o. midazolam (hepatic + intestinal CYP3A), (g) i.v. digoxin (hepatic P-gp), and (h) p.o. digoxin (hepatic + intestinal P-gp). i.v., intravenous; P-gp, P-glycoprotein; p.o., oral; TPV/r, tipranavir/ritonavir.
Figure 1
Figure 1
Concentration–time curve at baseline, after first dose, and at steady state of (a) caffeine (CYP1A2), (b) S-warfarin (CYP2C9), (c) omeprazole (CYP2C19), (d) dextromethorphan (CYP2D6), (e) i.v. midazolam (hepatic CYP3A), (f) p.o. midazolam (hepatic + intestinal CYP3A), (g) i.v. digoxin (hepatic P-gp), and (h) p.o. digoxin (hepatic + intestinal P-gp). i.v., intravenous; P-gp, P-glycoprotein; p.o., oral; TPV/r, tipranavir/ritonavir.
Figure 1
Figure 1
Concentration–time curve at baseline, after first dose, and at steady state of (a) caffeine (CYP1A2), (b) S-warfarin (CYP2C9), (c) omeprazole (CYP2C19), (d) dextromethorphan (CYP2D6), (e) i.v. midazolam (hepatic CYP3A), (f) p.o. midazolam (hepatic + intestinal CYP3A), (g) i.v. digoxin (hepatic P-gp), and (h) p.o. digoxin (hepatic + intestinal P-gp). i.v., intravenous; P-gp, P-glycoprotein; p.o., oral; TPV/r, tipranavir/ritonavir.
Figure 1
Figure 1
Concentration–time curve at baseline, after first dose, and at steady state of (a) caffeine (CYP1A2), (b) S-warfarin (CYP2C9), (c) omeprazole (CYP2C19), (d) dextromethorphan (CYP2D6), (e) i.v. midazolam (hepatic CYP3A), (f) p.o. midazolam (hepatic + intestinal CYP3A), (g) i.v. digoxin (hepatic P-gp), and (h) p.o. digoxin (hepatic + intestinal P-gp). i.v., intravenous; P-gp, P-glycoprotein; p.o., oral; TPV/r, tipranavir/ritonavir.
Figure 1
Figure 1
Concentration–time curve at baseline, after first dose, and at steady state of (a) caffeine (CYP1A2), (b) S-warfarin (CYP2C9), (c) omeprazole (CYP2C19), (d) dextromethorphan (CYP2D6), (e) i.v. midazolam (hepatic CYP3A), (f) p.o. midazolam (hepatic + intestinal CYP3A), (g) i.v. digoxin (hepatic P-gp), and (h) p.o. digoxin (hepatic + intestinal P-gp). i.v., intravenous; P-gp, P-glycoprotein; p.o., oral; TPV/r, tipranavir/ritonavir.
Figure 1
Figure 1
Concentration–time curve at baseline, after first dose, and at steady state of (a) caffeine (CYP1A2), (b) S-warfarin (CYP2C9), (c) omeprazole (CYP2C19), (d) dextromethorphan (CYP2D6), (e) i.v. midazolam (hepatic CYP3A), (f) p.o. midazolam (hepatic + intestinal CYP3A), (g) i.v. digoxin (hepatic P-gp), and (h) p.o. digoxin (hepatic + intestinal P-gp). i.v., intravenous; P-gp, P-glycoprotein; p.o., oral; TPV/r, tipranavir/ritonavir.
Figure 1
Figure 1
Concentration–time curve at baseline, after first dose, and at steady state of (a) caffeine (CYP1A2), (b) S-warfarin (CYP2C9), (c) omeprazole (CYP2C19), (d) dextromethorphan (CYP2D6), (e) i.v. midazolam (hepatic CYP3A), (f) p.o. midazolam (hepatic + intestinal CYP3A), (g) i.v. digoxin (hepatic P-gp), and (h) p.o. digoxin (hepatic + intestinal P-gp). i.v., intravenous; P-gp, P-glycoprotein; p.o., oral; TPV/r, tipranavir/ritonavir.
Figure 1
Figure 1
Concentration–time curve at baseline, after first dose, and at steady state of (a) caffeine (CYP1A2), (b) S-warfarin (CYP2C9), (c) omeprazole (CYP2C19), (d) dextromethorphan (CYP2D6), (e) i.v. midazolam (hepatic CYP3A), (f) p.o. midazolam (hepatic + intestinal CYP3A), (g) i.v. digoxin (hepatic P-gp), and (h) p.o. digoxin (hepatic + intestinal P-gp). i.v., intravenous; P-gp, P-glycoprotein; p.o., oral; TPV/r, tipranavir/ritonavir.
Figure 2
Figure 2
Study schematic. Dig, digoxin; i.v., intravenous; MDZ, midazolam; p.o., oral; TPV/r, tipranavir/ritonavir. *Subjects randomized to receive either oral or intravenous digoxin.
See this image and copyright information in PMC

References

    1. Derks M, Fowler S, Kuhlmann O. In vitro and in vivo assessment of the effect of dalcetrapib on a panel of CYP substrates. Curr Med Res Opin. 2009;25:891–902. - PubMed
    1. Johnson BM, et al. Evaluation of the drug interaction potential of aplaviroc, a novel human immunodefficiency virus entry inhibitor, using a modified cooperstown 5 + 1 cocktail. J Clin Pharmacol. 2006;46:577–587. - PubMed
    1. Lim ML, et al. Coadministration of lopinavir/ritonavir and phenytoin results in two-way drug interaction through cytochrome P-450 induction. J Acquir Immune Defic Syndr. 2004;36:1034–1040. - PubMed
    1. Shelepova T, et al. Effect of a triphasic oral contraceptive on drug-metabolizing enzyme activity as measured by the validated Cooperstown 5+1 cocktail. J Clin Pharmacol. 2005;45:1413–1421. - PubMed
    1. Yeh RF, et al. Lopinavir/ritonavir induces the hepatic activity of cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP1A2 but inhibits the hepatic and intestinal activity of CYP3A as measured by a phenotyping drug cocktail in healthy volunteers. J Acquir Immune Defic Syndr. 2006;42:52–60. - PubMed

Publication types

MeSH terms