RT Journal Article
SR Electronic
T1 EFFECT OF PROPIVERINE ON CYTOCHROME P450 ENZYMES: A COCKTAIL INTERACTION STUDY IN HEALTHY VOLUNTEERS
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1859
OP 1866
DO 10.1124/dmd.105.005272
VO 33
IS 12
A1 D. Tomalik-Scharte
A1 A. Jetter
A1 M. Kinzig-Schippers
A1 A. Skott
A1 F. Sörgel
A1 T. Klaassen
A1 D. Kasel
A1 S. Harlfinger
A1 O. Doroshyenko
A1 D. Frank
A1 J. Kirchheiner
A1 M. Bräter
A1 K. Richter
A1 T. Gramatté
A1 U. Fuhr
YR 2005
UL http://dmd.aspetjournals.org/content/33/12/1859.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics