gms | German Medical Science

Objective: 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 Gynecologists, 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, fesoterodine, oxybutynin, propiverine, solifenacin, tolterodine, trospium chloride.

Methods: To assess direct inhibition, an in vitro cocktail of seven specific, clinically relevant model substrates was incubated with pooled human liver microsomes for 10 minutes. For all experiments, the major metabolites of the probe substrates were simultaneously analyzed using a validated liquid chromatography - tandem mass spectrometry method and 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]. Subsequently to assess time-dependent inhibition, a single concentration equivalent to the IC₂₅, determined in the previous direct inhibition experiments, was used to examine TDI of the test compounds. After a 30 minute preincubation with NADPH, a TDI was identified by a decrease in enzyme activity.

Results: In this study 49 IC₅₀ experiments were conducted. In 8 out of these 49 cases point estimates for the IC₅₀ values were lower than the calculated threshold for DDIs in the gut wall. The strongest inhibition was observed for darifenacin, propiverine and tolterodine on CYP2D6 with the IC₅₀ values in the lower micromolar range (associated 95% confidence intervals): darifenacin 0.68 µM (0.42 µM-0.93 µM); propiverine 5.5 µM (3.7µM-6.8µM) and tolterodine 2.7µM (1.0µM-6.1µM). In the cases where an IC₅₀ value lower than the calculated threshold was observed, no increase in inhibition was determined after a 30 minute preincubation.

Conclusion: These screening experiments suggest that in particular darifenacin, propiverine and tolterodine 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 is currently gathered, allowing for physiologically based pharmacokinetic modeling.