Effect of verapamil on pharmacokinetics and pharmacodynamics of risperidone: In vivo evidence of involvement of P-glycoprotein in risperidone disposition

Objective: A recent in vitro study has shown that risperidone is a substrate of P-glycoprotein. The aim of this study was to confirm the effects of verapamil, a P-glycoprotein inhibitor, on the pharmacokinetics of risperidone. Methods: Two 6-day courses of either 240 rag verapamil daily, an inhibitor of P-glycoprotein, or placebo were administered in a randomized crossover fashion with at least a 4-week washout period. Twelve mate volunteers took a single oral 1-mg dose of risperidone on day 6 of both courses. Plasma concentrations of risperidone, 9-hydroxyrisperidone, and prolactin were monitored up to 24 hours after dosing. Results. Compared with placebo, verapamil treatment significantly increased the peak plasma concentration of risperidone by 1.8-fold and the area under the plasma concentration-time curve (AUC) from 0 to 24 hours of risperidone by 2.0-fold but did not alter the elimination half-life. The AUC from 0 to 24 hours of 9-hydroxyrisperidone, but not other pharmacokinetic parameters, was significantly increased during verapamil treatment. However, the AUC from 0 to 4 hours and the AUC from 0 to 8 hours of prolactin concentrations were not increased by verapamil treatment despite the pharmacokinetic alterations. Conclusion: This study demonstrated that the bioavailability of risperidone was increased by verapamil, suggesting in vivo involvement of P-glycoprotein in the pharmacokinetics of risperidone.