Influence of ABCB1 genetic polymorphisms on the pharmacokinetics of risperidone in healthy subjects with CYP2D6*10/*10

Yoo, Hee-Doo; Lee, Sang-No; Kang, Hyunah; Cho, Hea-Young; Lee, Il-Kwon; Lee, Yong-Bok

doi:10.1111/j.1476-5381.2011.01385.x

Cited by 41 publications

(27 citation statements)

References 42 publications

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“…In our study of the pharmacokinetics of risperidone according to genetic polymorphisms in CYP2D6 and ABCB1 (3435C > T and 2677G > T/A), there were no significant differences in the AUC of risperidone in the ABCB1 3435C > T genotypes (Yoo et al, 2011b). Unlike the single ABCB1 3435C > T genotypes, ABCB1 3435C > T genotypes in individuals with the CYP2D6 *10/*10 genotype were associated with statistically significant differences in the pharmacokinetic parameters of risperidone.…”

Section: Interplay Of Abcb1 Transporters and Cyp Enzymesmentioning

confidence: 66%

“…In our study, the pharmacokinetic parameters of levosulpiride in ABCB1 2677TT and 3435TT subjects were significantly higher than those of subjects with at least one wild-type allele . In addition, significant differences were observed between the ABCB1 3435C > T genotypes for the pharmacokinetic parameters of risperidone and the active moiety (risperidone and its main metabolite, 9-hydroxyrisperidone) (Yoo et al, 2011b). Brain concentrations of the active moiety were 10-fold higher in knockout than in wild-type animals.…”

Section: Abcb1 Transportersmentioning

confidence: 97%

“…The active moiety could be important for estimating the clinical effects of risperidone. The observed CYP2D6 polymorphisms may not contribute to altered clinical efficacy, but rather affect risperidone/ 9-hydroxyrisperidone ratios (Yoo et al, 2011b).…”

Section: Cytochrome P450 Enzymesmentioning

confidence: 99%

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Interplay of pharmacogenetic variations in ABCB1 transporters and cytochrome P450 enzymes

Yoo

Lee

2011

Arch. Pharm. Res.

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Interindividual variability in oral drug efficacy 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. Pharmacogenetics are rapidly elucidating the inherited nature of these differences in drug disposition and effects, thereby providing a stronger scientific basis for optimizing drug therapy on the basis of each patient's genetic constitution. Knowledge of the genotype-phenotype correlation and frequency distribution of functional single nucleotide polymorphisms may be a valuable tool for individualizing drug therapy. This information can also be useful for explaining inter-individual and inter-ethnic variations in drug response and/or adverse effects. In this review, we focus on the interplay between efflux transporter (ATP-binding cassette, sub-family B (MDR/TAP), member 1/ABCB1) and cytochrome P450s according to genetic polymorphism.

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Section: Interplay Of Abcb1 Transporters and Cyp Enzymesmentioning

confidence: 66%

Section: Abcb1 Transportersmentioning

confidence: 97%

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Interplay of pharmacogenetic variations in ABCB1 transporters and cytochrome P450 enzymes

Yoo

Lee

2011

Arch. Pharm. Res.

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“…peak serum concentration) of risperidone and the active moiety (risperidone and its main metabolite, 9-hydroxyrisperidone). Furthermore, single nucleotide polymorphisms (SNP) 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 [21].…”

Section: Risperidonementioning

confidence: 99%

Population pharmacokinetic analysis of risperidone and 9-hydroxyrisperidone with genetic polymorphisms of CYP2D6 and ABCB1

Yoo

Cho

Lee

et al. 2012

J Pharmacokinet Pharmacodyn

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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.

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“…9 However, studies of the effects of the ABCB1 genotype on RIS metabolism have provided controversial findings. 5Y7, 10,11 The aim of the present study was to investigate the effects of the CYP2D6 and ABCB1 gene polymorphisms on steadystate RIS, 9-OH-RIS, and total active moiety plasma levels in Japanese psychiatric patients.…”

mentioning

confidence: 99%

Impact of the ABCB1 Gene Polymorphism on Plasma 9-Hydroxyrisperidone and Active Moiety Levels in Japanese Patients With Schizophrenia

Suzuki

Tsuneyama

Fukui

et al. 2013

Journal of Clinical Psychopharmacology

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9-Hydroxyrisperidone (9-OH-RIS) is an active metabolite of the antipsychotic drug risperidone (RIS). The total active moiety level, in other words the sum of the RIS and 9-OH-RIS serum levels, may be important for estimating the clinical effects of RIS treatment. However, there have been no consistent results reported regarding the relationship between cytochrome P450 (CYP) 2D6 or adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) variant alleles and 9-OH-RIS or total active moiety plasma levels. Seventy-four Japanese patients treated with RIS were examined in the present study. Steady-state plasma RIS and 9-OH-RIS were measured. The CYP2D6*5, CYP2D6*10, ABCB1 3435C>T, and ABCB1 2677G>T/A genotypes were detected. Multiple regression analysis showed that the dose-corrected plasma RIS levels were significantly correlated with the number of CYP2D6 variant alleles and ABCB1 3435C>T genotypes, whereas the 9-OH-RIS and total active moiety levels were significantly correlated with the ABCB1 3435C>T genotypes and with age. On the other hand, the ABCB1 2677G>T/A genotypes did not affect plasma RIS, 9-OH-RIS, or total active moiety levels. The ABCB1 3435C>T genetic polymorphism may predict plasma 9-OH-RIS and total active moiety levels.

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Influence of ABCB1 genetic polymorphisms on the pharmacokinetics of risperidone in healthy subjects with *CYP2D6**10/*10

Cited by 41 publications

References 42 publications

Interplay of pharmacogenetic variations in ABCB1 transporters and cytochrome P450 enzymes

Interplay of pharmacogenetic variations in ABCB1 transporters and cytochrome P450 enzymes

Population pharmacokinetic analysis of risperidone and 9-hydroxyrisperidone with genetic polymorphisms of CYP2D6 and ABCB1

Impact of the ABCB1 Gene Polymorphism on Plasma 9-Hydroxyrisperidone and Active Moiety Levels in Japanese Patients With Schizophrenia

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