title: Population pharmacokinetic analysis of risperidone and 9-hydroxyrisperidone with genetic polymorphisms of CYP2D6 and ABCB1.
abstract: This study estimated the population pharmacokinetics of risperidone and its active metabolite, 9-hydroxyrisperidone, according to genetic polymorphisms in the metabolizing enzyme (CYP2D6) and transporter (ABCB1) genes in healthy subjects. Eighty healthy subjects who received a single oral dose of 2 mg risperidone participated in this study. However, eight subjects with rare genotype variants in CYP2D6 alleles were excluded from the final model built in this study. We conducted the population pharmacokinetic analysis of risperidone and 9-hydroxyrisperidone using a nonlinear mixed effects modeling (NONMEM) method and explored the possible influence of genetic polymorphisms in CYP2D6 alleles and ABCB1 (2677G>T/A and 3435C>T) on the population pharmacokinetics of risperidone and 9-hydroxyrisperidone. A two-compartment model with a first-order absorption and lag time fitted well to serum concentration-time curve for risperidone. 9-hydroxyrisperidone was well described by a one-compartment model as an extension of the parent drug (risperidone) model with first-order elimination and absorption partially from the depot. Significant covariates for risperidone clearance were genetic polymorphisms of CYP2D6*10, including CYP2D6*1/*10 (27.5 % decrease) and CYP2D6*10/*10 (63.8 % decrease). There was significant difference in the absorption rate constant (k                         (                            a                         )) of risperidone among the CYP2D6*10 genotype groups. In addition, combined ABCB1 3435C>T and CYP2D6*10 genotypes had a significant (P < 0.01) effect on the fraction of metabolite absorbed from the depot. The population pharmacokinetic model of risperidone and 9-hydroxyrisperidone including the genetic polymorphisms of CYP2D6*10 and ABCB1 3435C>T as covariates was successfully constructed. The estimated contribution of genetic polymorphisms in CYP2D6*10 and ABCB1 3435C>T to population pharmacokinetics of risperidone and 9-hydroxyrisperidone suggests the interplay of CYP2D6 and ABCB1 on the pharmacokinetics of risperidone and 9-hydroxyrisperidone according to genetic polymorphisms.
authors.affiliation: College of Pharmacy and Institute of Bioequivalence and Bridging Study, Chonnam National University, 300 Yongbong-Dong, Buk-Gu, Gwangju 500-757, Korea.
authors.forename: Hee-Doo
authors.initials: HD
authors.lastname: Yoo
authors.forename: Hea-Young
authors.initials: HY
authors.lastname: Cho
authors.forename: Sang-No
authors.initials: SN
authors.lastname: Lee
authors.forename: Hwa
authors.initials: H
authors.lastname: Yoon
authors.forename: Yong-Bok
authors.initials: YB
authors.lastname: Lee
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000483:Alleles; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D006801:Humans; D007555:Isoxazoles / Q000493:pharmacokinetics*; D008297:Male; D008954:Models, Biological; D000068882:Paliperidone Palmitate; D020641:Polymorphism, Single Nucleotide; D011743:Pyrimidines / Q000493:pharmacokinetics*; D018967:Risperidone / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007555:Isoxazoles; D011743:Pyrimidines; D019389:Cytochrome P-450 CYP2D6; D018967:Risperidone; D000068882:Paliperidone Palmitate