gms | German Medical Science

Aim: Approximately one in six adults in the United States and Europe suffer from overactive bladder syndrome (OAB) [1], [2]. In the latest guideline [3] issued by the German Society of Obstetricians and Gynaecologists, anticholinergic agents are stated as the pharmacotherapy of choice with seven drugs being approved for the German market. Yet, only limited information on the drug-drug interaction potential of these agents exists. Therefore, we examined inhibition of the seven major cytochrome P450 (CYP) enzymes by darifenacin, fesoterodin, oxybutinin, propiverin, solifenacin, tolterodin, trospium chloride.

Method: An in vitro cocktail of seven highly selective probe substrates at a single concentration 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 method. Subsequently, enzyme kinetics were estimated by determining IC₅₀ values. These IC₅₀ values were then converted to an inhibition constant Ki using the Cheng-Prusoff equation [4].

Results: In this study 49 IC₅₀ experiments were conducted. In 18 out of these 49 cases, point estimates for the IC₅₀ values were smaller than 100 µM. In these cases CYP2D6 and CYP3A4 were most frequently inhibited (5 cases for CYP2D6; 5 cases for CYP3A4). The strongest inhibition was observed for darifenacin, propiverin and tolterodin on CYP2D6 with the calculated Ki in the lower micromolar range (associated 95% confidence intervals): darifenacin 0.0053 µM (0.0032 µM–0.0075 µM); propiverin 1.9 µM (1.4 µM–2.3 µM) and tolterodin 2.7 µM (1.7 µM–3.6 µM).

Conclusion: These screening experiments suggest that in particular darifenacin, propiverin and tolterodin may have clinically relevant inhibitory effects on especially CYP2D6 in humans. To characterize the potential clinical impact of these interactions and recommend dosage modifications, further in vitro data needs to be gathered, allowing for physiologically based pharmacokinetic modelling.