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Drug Metabolism and Disposition Fast Forward
First published on September 23, 2005; DOI: 10.1124/dmd.105.005272

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Received for publication April 25, 2005.
Revised September 21, 2005.
Accepted for publication September 21, 2005.

Effect of propiverine on cytochrome P450 enzymes: a cocktail interaction study in healthy volunteers

Dorota Tomalik-Scharte 1*, Alexander Jetter 1, Martina Kinzig-Schippers 2, Andreas Skott 2, Fritz Sorgel 2, Tobias Klaassen 1, Dirk Kasel 1, Steffi Harlfinger 1, Oxana Doroshyenko 1, Doro Frank 1, Julia Kirchheiner 1, Manfred Brater 3, Klaus Richter 4, Thomas Gramatte 3, Uwe Fuhr 1

1 Department of Pharmacology, Clinical Pharmacology, University of Cologne, Germany 2 IBMP - Institute for Biomedical and Pharmaceutical Research, Nurnberg-Heroldsberg, Germany 3 APOGEPHA Arzneimittel GmbH, Dresden, Germany 4 Institute of Clinical Pharmacology, University of Technology Dresden, Department of Pharmacology, Ge

* Address correspondence to: E-mail: dorota.tomalik-scharte{at}uk-koeln.de

Abstract

The 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 3A4 and of hepatic CYP3A4, CYP2C9, CYP2C19 and CYP1A2. The activity of the respective CYPs 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 - 8 hours postdose (50 mg mephenytoin orally), and the paraxanthine/caffeine plasma ratio 6 hours postdose (150 mg caffeine orally). These metrics were determined in 16 healthy young men at the end of 7 days treatment with 15 mg of propiverine (Test) or placebo (Reference) twice daily. All phenotyping drugs were quantified by LC-MS/MS. Chronic propiverine treatment reduced hepatic and intestinal CYP3A4 activity slightly to 0.89-fold and 0.80-fold, respectively (90% 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 AUC 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.


Key words: cytochrome P450, drug-drug interactions


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