Influence of ABCB1 and CYP3A5 genetic polymorphisms on the pharmacokinetics of quetiapine in healthy volunteers

Kyoung Ah Kim, Hyun Jin Joo, Hae Mi Lee, Ji-Young Park

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

BACKGROUND AND OBJECTIVES: Quetiapine is an atypical antipsychotic drug used to treat schizophrenia and acute episodes of mania. Quetiapine is metabolized by CYP3A enzymes including CYP3A5 and is a substrate of P-glycoprotein, an efflux drug transporter encoded by the ABCB1 gene. We assessed the effects of ABCB1 [c.1236C>T (rs1128503), c.2677G>T/A (rs2032582), c.3435C>T (rs1045642)] and CYP3A5*3 (6986A>G) (rs776746) polymorphisms on the pharmacokinetics of quetiapine in humans. MATERIALS AND METHODS: Forty healthy male individuals were enrolled, and their ABCB1 and CYP3A5 polymorphisms were assessed. After a single dose of 100 mg quetiapine was administered, plasma concentrations of quetiapine were measured for 24 h and pharmacokinetic analysis was carried out. RESULTS: The ABCB1 polymorphisms including c.1236C>T, c.2677G>T/A, and c.3435C>>T did not affect plasma levels of quetiapine, and its pharmacokinetic parameters did not differ among ABCB1 genotype groups. However, the CYP3A5*3 polymorphism significantly affected the plasma level of quetiapine and its pharmacokinetics. The peak plasma concentration of quetiapine was 208.39 ng/ml for CYP3A5*1/*1, 243.46 ng/ml for CYP3A5*1/*3, and 332.94 ng/ml for CYP3A5*3/*3 (P=0.0118). The mean AUCinf (area under the time vs. concentration curve from 0 to infinity) value was 627.3, 712.77, and 1045.29 ng h/ml, respectively (P=0.0017). CONCLUSION: The results indicated that the genetic polymorphism of CYP3A5*3 but not ABCB1 significantly influences the plasma level of quetiapine and its pharmacokinetics. These findings suggest that the CYP3A5 genetic polymorphism affects the disposition of quetiapine and provide a plausible explanation for interindividual variation in the disposition of this drug.

Original languageEnglish
Pages (from-to)35-42
Number of pages8
JournalPharmacogenetics and Genomics
Volume24
Issue number1
DOIs
Publication statusPublished - 2014 Jan 1

Fingerprint

Cytochrome P-450 CYP3A
Genetic Polymorphisms
Healthy Volunteers
Pharmacokinetics
Quetiapine Fumarate
P-Glycoprotein
Bipolar Disorder
Pharmaceutical Preparations
Antipsychotic Agents
Schizophrenia
Genotype

Keywords

  • ABCB1
  • CYP3A5
  • P-glycoprotein
  • Pharmacokinetics
  • Quetiapine

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Influence of ABCB1 and CYP3A5 genetic polymorphisms on the pharmacokinetics of quetiapine in healthy volunteers. / Kim, Kyoung Ah; Joo, Hyun Jin; Lee, Hae Mi; Park, Ji-Young.

In: Pharmacogenetics and Genomics, Vol. 24, No. 1, 01.01.2014, p. 35-42.

Research output: Contribution to journalArticle

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T1 - Influence of ABCB1 and CYP3A5 genetic polymorphisms on the pharmacokinetics of quetiapine in healthy volunteers

AU - Kim, Kyoung Ah

AU - Joo, Hyun Jin

AU - Lee, Hae Mi

AU - Park, Ji-Young

PY - 2014/1/1

Y1 - 2014/1/1

N2 - BACKGROUND AND OBJECTIVES: Quetiapine is an atypical antipsychotic drug used to treat schizophrenia and acute episodes of mania. Quetiapine is metabolized by CYP3A enzymes including CYP3A5 and is a substrate of P-glycoprotein, an efflux drug transporter encoded by the ABCB1 gene. We assessed the effects of ABCB1 [c.1236C>T (rs1128503), c.2677G>T/A (rs2032582), c.3435C>T (rs1045642)] and CYP3A5*3 (6986A>G) (rs776746) polymorphisms on the pharmacokinetics of quetiapine in humans. MATERIALS AND METHODS: Forty healthy male individuals were enrolled, and their ABCB1 and CYP3A5 polymorphisms were assessed. After a single dose of 100 mg quetiapine was administered, plasma concentrations of quetiapine were measured for 24 h and pharmacokinetic analysis was carried out. RESULTS: The ABCB1 polymorphisms including c.1236C>T, c.2677G>T/A, and c.3435C>>T did not affect plasma levels of quetiapine, and its pharmacokinetic parameters did not differ among ABCB1 genotype groups. However, the CYP3A5*3 polymorphism significantly affected the plasma level of quetiapine and its pharmacokinetics. The peak plasma concentration of quetiapine was 208.39 ng/ml for CYP3A5*1/*1, 243.46 ng/ml for CYP3A5*1/*3, and 332.94 ng/ml for CYP3A5*3/*3 (P=0.0118). The mean AUCinf (area under the time vs. concentration curve from 0 to infinity) value was 627.3, 712.77, and 1045.29 ng h/ml, respectively (P=0.0017). CONCLUSION: The results indicated that the genetic polymorphism of CYP3A5*3 but not ABCB1 significantly influences the plasma level of quetiapine and its pharmacokinetics. These findings suggest that the CYP3A5 genetic polymorphism affects the disposition of quetiapine and provide a plausible explanation for interindividual variation in the disposition of this drug.

AB - BACKGROUND AND OBJECTIVES: Quetiapine is an atypical antipsychotic drug used to treat schizophrenia and acute episodes of mania. Quetiapine is metabolized by CYP3A enzymes including CYP3A5 and is a substrate of P-glycoprotein, an efflux drug transporter encoded by the ABCB1 gene. We assessed the effects of ABCB1 [c.1236C>T (rs1128503), c.2677G>T/A (rs2032582), c.3435C>T (rs1045642)] and CYP3A5*3 (6986A>G) (rs776746) polymorphisms on the pharmacokinetics of quetiapine in humans. MATERIALS AND METHODS: Forty healthy male individuals were enrolled, and their ABCB1 and CYP3A5 polymorphisms were assessed. After a single dose of 100 mg quetiapine was administered, plasma concentrations of quetiapine were measured for 24 h and pharmacokinetic analysis was carried out. RESULTS: The ABCB1 polymorphisms including c.1236C>T, c.2677G>T/A, and c.3435C>>T did not affect plasma levels of quetiapine, and its pharmacokinetic parameters did not differ among ABCB1 genotype groups. However, the CYP3A5*3 polymorphism significantly affected the plasma level of quetiapine and its pharmacokinetics. The peak plasma concentration of quetiapine was 208.39 ng/ml for CYP3A5*1/*1, 243.46 ng/ml for CYP3A5*1/*3, and 332.94 ng/ml for CYP3A5*3/*3 (P=0.0118). The mean AUCinf (area under the time vs. concentration curve from 0 to infinity) value was 627.3, 712.77, and 1045.29 ng h/ml, respectively (P=0.0017). CONCLUSION: The results indicated that the genetic polymorphism of CYP3A5*3 but not ABCB1 significantly influences the plasma level of quetiapine and its pharmacokinetics. These findings suggest that the CYP3A5 genetic polymorphism affects the disposition of quetiapine and provide a plausible explanation for interindividual variation in the disposition of this drug.

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KW - Pharmacokinetics

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