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EFFECT OF PROPIVERINE ON CYTOCHROME P450 ENZYMES: A COCKTAIL INTERACTION STUDY IN HEALTHY VOLUNTEERS

Department of Pharmacology, Clinical Pharmacology, University of Cologne, Cologne, Germany (D.T.-S., A.J., T.K., D.K., S.H., O.D., D.F., J.K., U.F.); Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, Germany (M.K.-S., A.S., F.S.); APOGEPHA Arzneimittel GmbH, Dresden, Germany (M.B., T.G.); Institute of Clinical Pharmacology, University of Technology Dresden, Department of Pharmacology, Dresden, Germany (K.R.); and University of Duisburg-Essen, Duisburg-Essen, Germany (F.S.)

The present study was conducted to assess a possible in vivo effect of propiverine, an anticholinergic drug to treat urinary incontinence and related disorders, on the activity of intestinal CYP3A4 and of hepatic CYP3A4, CYP2C9, CYP2C19, and CYP1A2. The activity of the respective cytochromes P450 was measured using the following metrics of selective substrates given as a tailored low-dose phenotyping cocktail: intestinal availability of midazolam (2 mg orally), clearance of midazolam (1 mg i.v.), apparent clearance of tolbutamide (125 mg orally), urinary excretion of 4'-hydroxymephenytoin 0 to 8 h postdose (50 mg of mephenytoin orally), and the paraxanthine/caffeine plasma ratio 6 h postdose (150 mg of caffeine orally). These metrics were determined in 16 healthy young men at the end of 7 days of treatment with 15 mg of propiverine (test) or placebo (reference) twice daily. All phenotyping drugs were quantified by liquid chromatography-tandem mass spectrometry. Chronic propiverine treatment reduced hepatic and intestinal CYP3A4 activity slightly to 0.89-fold and 0.80-fold, respectively [90% confidence interval (CI) for test/reference ratios 0.85–0.93 and 0.72–0.89], with the combined effect resulting in a 1.46-fold increase in area under the curve of oral midazolam (90% CI 1.36–1.57). Propiverine had no relevant effect on CYP2C9, CYP2C19, and CYP1A2 (90% CI for test/reference ratios 0.93–1.00, 0.84–0.96, and 0.97–1.07, respectively). All study drugs were well tolerated. In conclusion, propiverine has a minor potential to cause drug-drug interactions.

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