Effect of genetic polymorphisms on the interplay of P-glycoprotein transporter and cytochrome P450 enzymes:Pharmacokinetics of risperidone

Yong-Bok Lee

College of Pharmacy,Chonnam National University,Gwangju 500-757,South Korea

Effect of genetic polymorphisms on the interplay of P-glycoprotein transporter and cytochrome P450 enzymes:Pharmacokinetics of risperidone

Yong-Bok Lee*

College of Pharmacy,Chonnam National University,Gwangju 500-757,South Korea

A R T I C L E I N F O

Article history:

Available online 23 November 2015

Genetic polymorphism

ABCB1

CYP2D6

Risperidone

Population pharmacokinetics

Inter-individual variability in oral drug effcacy and toxicity is commonly observed in all therapeutic areas.Importantly,interindividual variability in drug uptake and metabolism can result in poor drug response,adverse drug reactions,or unfavorable drug–drug interaction.One of the common causes of individual variations in drug response is genetic variation of drug transporters and metabolizing enzymes[1,2].We focus on the interplay between effux transporter(ATP-binding cassette,subfamily B(MDR/TAP),member 1/ABCB1)and cytochrome P450s according to genetic polymorphism[3].The objective of this lecture is to investigate the combined infuence of genetic polymorphisms in ABCB1 and CYP2D6 genes on risperidone pharmacokinetics[4].

Eighty healthy subjects who received a single oral dose of 2 mg risperidone participated 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 infuence of genetic polymorphisms in CYP2D6 alleles and ABCB1 (2677G>T/A and 3435C>T)on the population pharmacokinetics of risperidone and 9-hydroxyrisperidone.

Signifcant differences were observed between the ABCB1 3435C>T genotypes for the pharmacokinetic parameters(Cmax) of risperidone and the active moiety(risperidone and its main metabolite,9-hydroxyrisperidone).There were no signifcant differences in theAUC of risperidone and the active moiety among the ABCB1 2677G>T/A and 3435C>T genotypes.However,the CmaxandAUC were signifcantly different(P<0.001 and P=0.002 for risperidone,and P=0.018 and P=0.038 for the active moiety) among ABCB1 3435C>T genotypes in CYP2D6*10/*10.

Fig.1–Hypothetical interplay of P-gp and CYP enzymes according to genetic polymorphisms in the enterocytes. UM,ultra-metabolizers;EM,extensive metabolizers;IM, intermediate metabolizers;PM,poor metabolizers(cited from Reference[3]).

A two-compartment model with a frst-order absorption and lag time ftted well to serum concentration–time curve for risperidone.9-hydroxyrisperidone was well described by a onecompartment model as an extension of the parent drug (risperidone)model with frst-order elimination and absorption partially from the depot.Signifcant 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 signifcant difference in the absorption rate constant(ka)of risperidone among the CYP2D6*10 genotype groups.In addition,combined ABCB1 3435C>T and CYP2D6*10 genotypes had a signifcant(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[4].

Fig.1 illustrates a summary of the interplay of CYP2D6 and ABCB1 at enterocytes on the pharmacokinetics of risperidone and 9-hydroxyrisperidone according to genetic polymorphisms and indicates that the interplay has an important physiological role as“a functional barrier”,pumping out not only parent drug,but also metabolites generated in the enterocytes.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 andABCB1 on the pharmacokinetics of risperidone and 9-hydroxyrisperidone according to genetic polymorphisms.These fndings indicate that polymorphisms of ABCB1 3435C>T in individuals with CYP2D6*10/*10,which has low metabolic activity, could play an important role in the potential adverse effects or toxicity of risperidone[4].

R E F E R E N C E S

[1]Yoo HD,Park SA,Cho HY,et al.Infuence of CYP3A and CYP2C19 genetic polymorphisms on the pharmacokinetics of cilostazol in healthy subjects.Clin Pharmacol Ther 2009;86:281–284.

[2]Yoo HD,Cho HY,Lee YB.Population pharmacokinetic analysis of cilostazol in healthy subjects with genetic polymorphisms of CYP3A5,CYP2C19 and ABCB1.Br J Clin Pharmacol 2010;69:27–37.

[3]Yoo HD,Lee YB.Interplay of ABCB1 transporters and cytochrome P450 enzymes according to genetic polymorphism.Arch Pharm Res 2011;34:1817–1828.

[4]Yoo HD,Lee SN,Kang HA,et al.Infuence of ABCB1 genetic polymorphisms on the pharmacokinetics of risperidone in healthy subjects with CYP2D6*10/*10.Br J Pharmacol 2011;164:433–443.

*E-mail address:leeyb@chonnam.ac.kr.

Peer review under responsibility of Shenyang Pharmaceutical University.

http://dx.doi.org/10.1016/j.ajps.2015.10.021

1818-0876/©2016 The Author.Production and hosting by Elsevier B.V.on behalf of Shenyang Pharmaceutical University.This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).