Dahlinger, Dominik, Aslan, Sevinc, Pietsch, Markus, Frechen, Sebastian and Fuhr, Uwe (2017). Assessment of inhibitory effects on major human cytochrome P450 enzymes by spasmolytics used in the treatment of overactive bladder syndrome. Ther. Adv. Urol., 9 (7). S. 163 - 178. LONDON: SAGE PUBLICATIONS LTD. ISSN 1756-2880

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Abstract

Background: The objective of this study was to examine the inhibitory potential of darifenacin, fesoterodine, oxybutynin, propiverine, solifenacin, tolterodine and trospium chloride on the seven major human cytochrome P450 enzymes (CYP) by using a standardized and validated seven-in-one cytochrome P450 cocktail inhibition assay. Methods: An in vitro cocktail of seven highly selective probe substrates was incubated with human liver microsomes and varying concentrations of the seven test compounds. The major metabolites of the probe substrates were simultaneously analysed using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Enzyme kinetics were estimated by determining IC50 and K-i values via nonlinear regression. Obtained K-i values were used for predictions of potential clinical impact of the inhibition using a static mechanistic prediction model. Results: In this study, 49 IC50 experiments were conducted. In six cases, IC50 values lower than the calculated threshold for drug-drug interactions (DDIs) in the gut wall were observed. In these cases, no increase in inhibition was determined after a 30 min preincubation. Considering a typical dosing regimen and applying the obtained K-i values of 0.72 mu M (darifenacin, 15 mg daily) and 7.2 mu M [propiverine, 30 mg daily, immediate release (IR)] for the inhibition of CYP2D6 yielded a predicted 1.9-fold and 1.4-fold increase in the area under the curve (AUC) of debrisoquine (CYP2D6 substrate), respectively. Due to the inhibition of the particular intestinal CYP3A4, the obtained K-i values of 14 mu M of propiverine (30 mg daily, IR) resulted in a predicted doubling of the AUC for midazolam (CYP3A4 substrate). Conclusions:In vitro/in vivo extrapolation based on pharmacokinetic data and the conducted screening experiments yielded similar effects of darifenacin on CYP2D6 and propiverine on CYP3A4 as obtained in separately conducted in vivo DDI studies. As a novel finding, propiverine was identified to potentially inhibit CYP2D6 at clinically occurring concentrations.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Dahlinger, DominikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aslan, SevincUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pietsch, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frechen, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fuhr, UweUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-226273
DOI: 10.1177/1756287217708951
Journal or Publication Title: Ther. Adv. Urol.
Volume: 9
Number: 7
Page Range: S. 163 - 178
Date: 2017
Publisher: SAGE PUBLICATIONS LTD
Place of Publication: LONDON
ISSN: 1756-2880
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DRUG-DRUG INTERACTIONS; HUMAN LIVER-MICROSOMES; CLINICAL PHARMACOKINETICS; TROSPIUM CHLORIDE; METABOLISM; PHARMACOLOGY; PROPIVERINE; ELIMINATION; SOLIFENACIN; POPULATIONMultiple languages
Urology & NephrologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/22627

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