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 mg 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 male 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.


CONCLUSIONS
This study demonstrated that the bioavailability of risperidone was increased by verapamil, suggesting in vivo involvement of P-glycoprotein in the pharmacokinetics of risperidone.
Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki 036-8562, Japan.
Taku
T
Nakagami
Norio
N
Yasui-Furukori
Manabu
M
Saito
Tomonori
T
Tateishi
Sunao
S
Kaneo
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000378:metabolism*; D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D002853:Chromatography, Liquid / Q000379:methods; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005838:Genotype; D006207:Half-Life; D006801:Humans; D007124:Immunoenzyme Techniques / Q000379:methods; D007555:Isoxazoles / Q000097:blood / Q000494:pharmacology; D007564:Japan / Q000208:ethnology; D008297:Male; D000068882:Paliperidone Palmitate; D018579:Patient Selection; D011388:Prolactin / Q000097:blood / Q000187:drug effects; D011743:Pyrimidines / Q000097:blood / Q000494:pharmacology; D018967:Risperidone / Q000493:pharmacokinetics* / Q000494:pharmacology; D013223:Statistics as Topic / Q000379:methods; D014700:Verapamil / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007555:Isoxazoles; D011743:Pyrimidines; D011388:Prolactin; D014700:Verapamil; D019389:Cytochrome P-450 CYP2D6; D018967:Risperidone; D000068882:Paliperidone Palmitate