Effect of ABCG2 genotypes on the pharmacokinetics of A771726, an active metabolite of prodrug leflunomide, and association of A771726 exposure with serum uric acid level

Kyoung Ah Kim, Hyun Jin Joo, Ji-Young Park

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Objective: It has been reported that leflunomide and its active metabolite, A771726, are substrates of the ABCG2 (BCRP) transporter in vitro. Recent genome-wide association studies have shown that ABCG2 transporter modulates serum uric acid (UA) levels. We explored the role of ABCG2 genotypes in the pharmacokinetics of A771726 and the relationship between serum UA levels and pharmacokinetics of A771726 in healthy participants. Methods: Twenty-four healthy individuals were recruited and genotyped for ABCG2. After administration of a single dose of 20 mg leflunomide, plasma concentrations of A771726 were measured. Serum UA levels were measured just before medication, and ABCG2 c.421C>A and c.34G> A polymorphism were genotyped. Results: ABCG2 c.421C>A but not c.34G>A substantially influenced the pharmacokinetics of A771726. A771726 Cmax was 30% higher, area under the concentration-time curve (AUC) 83% larger, and oral clearance (CL/F) 41% lower in c.421C>A carriers than in noncarriers. Serum UA levels were also higher in carriers than in noncarriers and exhibited a strong and positive correlation with A771726 AUC (Spearman r=0.6746, P=0.0003), but a negative correlation was observed with A771726 CL/F (Spearman r=-0.6616, P=0.0004). Conclusion: ABCG2 c.421C>A but not c.34G>A polymorphism appears to be a major determinant of interindividual variability in A771726 disposition. Additionally, serum UA levels exhibited a strong correlation with exposure to A771726.

Original languageEnglish
Pages (from-to)129-134
Number of pages6
JournalEuropean Journal of Clinical Pharmacology
Volume67
Issue number2
DOIs
Publication statusPublished - 2011 Feb 1

Fingerprint

leflunomide
A 771726
Prodrugs
Uric Acid
Pharmacokinetics
Genotype
Serum
Genome-Wide Association Study

Keywords

  • A771726
  • ABCG2
  • BCRP
  • Leflunomide
  • Uric acid

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

@article{6fdc80bc469b41bba14467fc073af009,
title = "Effect of ABCG2 genotypes on the pharmacokinetics of A771726, an active metabolite of prodrug leflunomide, and association of A771726 exposure with serum uric acid level",
abstract = "Objective: It has been reported that leflunomide and its active metabolite, A771726, are substrates of the ABCG2 (BCRP) transporter in vitro. Recent genome-wide association studies have shown that ABCG2 transporter modulates serum uric acid (UA) levels. We explored the role of ABCG2 genotypes in the pharmacokinetics of A771726 and the relationship between serum UA levels and pharmacokinetics of A771726 in healthy participants. Methods: Twenty-four healthy individuals were recruited and genotyped for ABCG2. After administration of a single dose of 20 mg leflunomide, plasma concentrations of A771726 were measured. Serum UA levels were measured just before medication, and ABCG2 c.421C>A and c.34G> A polymorphism were genotyped. Results: ABCG2 c.421C>A but not c.34G>A substantially influenced the pharmacokinetics of A771726. A771726 Cmax was 30{\%} higher, area under the concentration-time curve (AUC) 83{\%} larger, and oral clearance (CL/F) 41{\%} lower in c.421C>A carriers than in noncarriers. Serum UA levels were also higher in carriers than in noncarriers and exhibited a strong and positive correlation with A771726 AUC (Spearman r=0.6746, P=0.0003), but a negative correlation was observed with A771726 CL/F (Spearman r=-0.6616, P=0.0004). Conclusion: ABCG2 c.421C>A but not c.34G>A polymorphism appears to be a major determinant of interindividual variability in A771726 disposition. Additionally, serum UA levels exhibited a strong correlation with exposure to A771726.",
keywords = "A771726, ABCG2, BCRP, Leflunomide, Uric acid",
author = "Kim, {Kyoung Ah} and Joo, {Hyun Jin} and Ji-Young Park",
year = "2011",
month = "2",
day = "1",
doi = "10.1007/s00228-010-0916-0",
language = "English",
volume = "67",
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T1 - Effect of ABCG2 genotypes on the pharmacokinetics of A771726, an active metabolite of prodrug leflunomide, and association of A771726 exposure with serum uric acid level

AU - Kim, Kyoung Ah

AU - Joo, Hyun Jin

AU - Park, Ji-Young

PY - 2011/2/1

Y1 - 2011/2/1

N2 - Objective: It has been reported that leflunomide and its active metabolite, A771726, are substrates of the ABCG2 (BCRP) transporter in vitro. Recent genome-wide association studies have shown that ABCG2 transporter modulates serum uric acid (UA) levels. We explored the role of ABCG2 genotypes in the pharmacokinetics of A771726 and the relationship between serum UA levels and pharmacokinetics of A771726 in healthy participants. Methods: Twenty-four healthy individuals were recruited and genotyped for ABCG2. After administration of a single dose of 20 mg leflunomide, plasma concentrations of A771726 were measured. Serum UA levels were measured just before medication, and ABCG2 c.421C>A and c.34G> A polymorphism were genotyped. Results: ABCG2 c.421C>A but not c.34G>A substantially influenced the pharmacokinetics of A771726. A771726 Cmax was 30% higher, area under the concentration-time curve (AUC) 83% larger, and oral clearance (CL/F) 41% lower in c.421C>A carriers than in noncarriers. Serum UA levels were also higher in carriers than in noncarriers and exhibited a strong and positive correlation with A771726 AUC (Spearman r=0.6746, P=0.0003), but a negative correlation was observed with A771726 CL/F (Spearman r=-0.6616, P=0.0004). Conclusion: ABCG2 c.421C>A but not c.34G>A polymorphism appears to be a major determinant of interindividual variability in A771726 disposition. Additionally, serum UA levels exhibited a strong correlation with exposure to A771726.

AB - Objective: It has been reported that leflunomide and its active metabolite, A771726, are substrates of the ABCG2 (BCRP) transporter in vitro. Recent genome-wide association studies have shown that ABCG2 transporter modulates serum uric acid (UA) levels. We explored the role of ABCG2 genotypes in the pharmacokinetics of A771726 and the relationship between serum UA levels and pharmacokinetics of A771726 in healthy participants. Methods: Twenty-four healthy individuals were recruited and genotyped for ABCG2. After administration of a single dose of 20 mg leflunomide, plasma concentrations of A771726 were measured. Serum UA levels were measured just before medication, and ABCG2 c.421C>A and c.34G> A polymorphism were genotyped. Results: ABCG2 c.421C>A but not c.34G>A substantially influenced the pharmacokinetics of A771726. A771726 Cmax was 30% higher, area under the concentration-time curve (AUC) 83% larger, and oral clearance (CL/F) 41% lower in c.421C>A carriers than in noncarriers. Serum UA levels were also higher in carriers than in noncarriers and exhibited a strong and positive correlation with A771726 AUC (Spearman r=0.6746, P=0.0003), but a negative correlation was observed with A771726 CL/F (Spearman r=-0.6616, P=0.0004). Conclusion: ABCG2 c.421C>A but not c.34G>A polymorphism appears to be a major determinant of interindividual variability in A771726 disposition. Additionally, serum UA levels exhibited a strong correlation with exposure to A771726.

KW - A771726

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KW - BCRP

KW - Leflunomide

KW - Uric acid

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JO - European Journal of Clinical Pharmacology

JF - European Journal of Clinical Pharmacology

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