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Effect of polymorphisms on the pharmacokinetics, pharmacodynamics, and safety of risperidone in healthy volunteers
Author(s) -
Cabaleiro Teresa,
Ochoa Dolores,
LópezRodríguez Rosario,
Román Manuel,
Novalbos Jesús,
Ayuso Carmen,
AbadSantos Francisco
Publication year - 2014
Publication title -
human psychopharmacology: clinical and experimental
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.461
H-Index - 78
eISSN - 1099-1077
pISSN - 0885-6222
DOI - 10.1002/hup.2420
Subject(s) - risperidone , pharmacokinetics , cyp2d6 , medicine , pharmacodynamics , pharmacology , cyp2c19 , adverse effect , schizophrenia (object oriented programming) , psychiatry , cytochrome p450 , metabolism
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 1 mg 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 C max , area under the curve (AUC), and t 1/2 , as well as lower clearance. They also showed lower C max and AUC and higher t 1/2 for hydroxyrisperidone. Furthermore, individuals with a mutant VKORC1 genotype had a lower risperidone AUC and t 1/2 and higher clearance. The hydroxyrisperidone AUC was lower in individuals with the COMT mutant genotype. Risperidone increased prolactin levels (iAUC and iC max ), 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. Copyright © 2014 John Wiley & Sons, Ltd.