Effect of polymorphisms on the pharmacokinetics, pharmacodynamics, and safety of risperidone in healthy volunteers.

OBJECTIVE

To identify genetic markers capable of predicting the pharmacokinetics, pharmacodynamics, and adverse effects of risperidone.

METHODS

Genotyping was performed in 70 healthy volunteers receiving a single 1mg oral dose of risperidone. Risperidone and hydroxyrisperidone plasma levels were measured using high-performance liquid chromatography combined with tandem mass spectrometry.Prolactin concentration was quantified by direct chemiluminescence.

RESULTS

Poor CYP2D6 metabolizers showed higher risperidone Cmax, area under the curve (AUC), and t1/2, as well as lower clearance. They also showed lower Cmax and AUC and higher t1/2 for hydroxyrisperidone. Furthermore, individuals with a mutant VKORC1 genotype had a lower risperidone AUC and t1/2 and higher clearance. The hydroxyrisperidone AUC was lower in individuals with the COMT mutant genotype. Risperidone increased prolactin levels (iAUC and iCmax), which were higher in women than in men. The most frequent reactions were somnolence (47.1%), headache (21.4%), and dizziness (17.1%). Women had neurological effects and headache more frequently than men. The incidence of headache was associated with polymorphisms in the AGTR1 and NAT2; neurological effects were associated with CYP2C19.

CONCLUSIONS

Differences in the pharmacokinetics of risperidone are due to polymorphisms in CYP2D6, COMT, and VKORC1. Differences in adverse reactions can be explained by gender and polymorphisms in CYP2C19, AGTR1, and NAT2.