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

• Published in: Drug metabolism and disposition Vol. 33; no. 12; pp. 1859 - 1866
• Main Authors: Tomalik-Scharte, D, Jetter, A, Kinzig-Schippers, M, Skott, A, Sörgel, F, Klaassen, T, Kasel, D, Harlfinger, S, Doroshyenko, O, Frank, D, Kirchheiner, J, Bräter, M, Richter, K, Gramatté, T, Fuhr, U
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01-12-2005
• Subjects: Adult; Aryl Hydrocarbon Hydroxylases - metabolism; Benzilates - pharmacology; Biological and medical sciences; Cross-Over Studies; Cytochrome P-450 CYP1A2 - metabolism; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - metabolism; Drug Interactions; Humans; Male; Medical sciences; Mixed Function Oxygenases - metabolism; Pharmacology. Drug treatments; Human; Healthy subject; Antispasmodic agent; Enzyme; Cytochrome P450; Interaction; Propiverine; Parasympatholytic
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.105.005272

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.