Effects of CYP2D6 Genotype on the Pharmacokinetics, Pharmacodynamics, and Safety of Risperidone in Healthy Volunteers

Abstract

The objective of this study was to analyze the relationship between CYP2D6 genotype and pharmacokinetics and pharmacodynamics of risperidone. Seventy-one healthy volunteers (36 women and 35 men) received a 1-mg single oral dose of risperidone. Six major CYP2D6 polymorphisms (CYP2D6*3, *4, *5, *6, *7, and *9) and the duplication were detected. Subjects were classified into 4 phenotypic groups: 6 ultrarapid (UMs), 34 extensive (EMs), 25 intermediate (IMs), and 6 poor metabolizers (PMs). There was a clear relationship between the number of active alleles and the pharmacokinetic parameters for risperidone and 9-hydroxyrisperidone, but there were no differences for total active moiety. Area under the curve and half-life of risperidone were significantly higher in PMs and IMs compared with EMs and UMs, which showed higher area under the curve of 9-hydroxyrisperidone. Risperidone produced a small decrease in blood pressure, a mild increase in QTc and a quick increase in prolactin, without significant differences between groups. Surprisingly, the incidence of adverse reactions was lower in PMs (50%) than in other subjects (78%). In conclusion, metabolism of risperidone depends on the number of active CYP2D6 alleles. So, PM subjects show higher concentrations of risperidone and very low concentrations of 9-hydroxyrisperidone. On the contrary, EM and UM subjects show low concentrations of risperidone and high concentrations of 9-hydroxyrisperidone. However, no major pharmacodynamic differences are observed between CYP2D6 genotypes, presumably because of the similar pharmacological activity of parent drug and metabolite.

DRD2 Taq1A Polymorphism Modulates Prolactin Secretion Induced by Atypical Antipsychotics in Healthy Volunteers

“…Recently, our group has studied the role of CYP2D6 polymorphisms related to prolactin secretion after a single dose of risperidone in healthy volunteers, showing that poor metabolizers displayed prolactin released slightly higher than other CYP2D6 phenotypes, although this difference did not reach statistical significance. 21 Multidrug-resistant protein 1 polymorphisms (MDR1) have also been studied, because of their role in antipsychotic absorption and/or distribution. Yasui-Furukori et al 39 studied the association between prolactin plasma concentration and 2 polymorphisms of MDR1 (C3435T and G2677T/A) and concluded that these variants are not associated with the plasma concentration of prolactin.…”

“…21 Pharmacokinetic parameters for quetiapine, olanzapine, risperidone, and 9-hydroxyrisperidone were calculated by noncompartmental methods. All calculations were carried out using WinNonlin 2.0 (Scientific Consulting, Inc, Palo Alto, Calif ).…”

CYP2D6 polymorphisms and their influence on risperidone treatment

“…This result exhibits increased CYP2D6 enzyme activity and leads to higher plasma drug concentration in prodrug or lower plasma drug concentration in active drugs. Furthermore, functional alterations of CYP2D6 variants have been widely studied in the Japanese population, but the results remain inconsistent 16,21,39,40. Cassandra Willyard et al41 suggested that the effect of CNV in a polymorphism was studied extensively because of its close association with drug metabolism, but many scientists still overlooked the importance and influence of gene duplication, deletion, and multiplication on drug response, although CNV has been used to understand the full spectrum of human genetic variation and also to assess the significance of such variation in disease association studies.…”

Investigation of the effect of solubility increase at the main absorption site on bioavailability of BCS class II drug (risperidone) using liquisolid technique

“…Its bioavailability is about 70% with high protein binding ability (88%). It is extremely metabolized in liver to the active metabolite 9-hydroxyrisperidone (Novalbos et al, 2010).…”