Responsiveness to low-dose warfarin associated with genetic variants of VKORC1, CYP2C9, CYP2C19, and CYP4F2 in an Indonesian population

T. Rusdiana, T. Araki, Tomonori Nakamura, A. Subarnas, K. Yamamoto

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Abstract

Purpose: The aim of this study was to assess the pharmacokinetics and pharmacodynamics of warfarin associated with genetic polymorphisms in VKORC1, CYP2C9, CYP2C19, and CYP4F2 in Indonesian patients treated with low-dose warfarin. Methods: Genotyping of VKORC1, CYP2C9, CYP2C19, and CYP4F2 was carried out in 103 patients treated with a daily dose of 1-2 mg warfarin, 89 of whom were treated with a fixed daily dose of warfarin (1 mg). The plasma concentrations of S- and R-warfarin and S- and R-7-hydroxywarfarin were used as pharmacokinetic indices, while prothrombin time expressed as the international normalized ratio (PT-INR) was used as a pharmacodynamic index. Results: In patients treated with a fixed daily dose of warfarin (1 mg), a higher PT-INR was associated with VKORC1-1639 AA [median 1.35; interquartile range (IQR) 1.21-1.50] than with the GA (1.18; IQR 1.12-1.32; p < 0.01) and GG (1.02; IQR = 1.02-1.06; p < 0.01) polymorphisms, and with CYP2C9*1/*3 (1.63; IQR 1.45-1.85) compared to*1/*1 (1.23; IQR 1.13-1.43; p < 0.05). The S-warfarin concentration was significantly higher in patients with CYP2C9*1/*3 than in those with*1/*1 (p < 0.05). With low-dose warfarin administration, there was no significant difference in the concentrations of warfarin metabolites among any of the genotype variants. The genotype variations of CYP2C19 and CYP4F2 were not significantly associated with the PT-INR. Conclusion: For low-dose warfarin treatment, the VKORC1-1639 G > A and CYP2C9 genotype variations affected the pharmacokinetics and pharmacodynamics of warfarin, while we could not find significant effects of CYP4F2 or CYP2C19 genotype variations on warfarin (metabolite) concentrations or PT-INR.

Original languageEnglish
Pages (from-to)395-405
Number of pages11
JournalEuropean Journal of Clinical Pharmacology
Volume69
Issue number3
DOIs
Publication statusPublished - 2013 Mar
Externally publishedYes

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Warfarin
International Normalized Ratio
Population
Pharmacokinetics
Genotype
Cytochrome P-450 CYP2C9
Cytochrome P-450 CYP2C19
Prothrombin Time
Genetic Polymorphisms

Keywords

  • CYP2C9
  • CYP4F2
  • Pharmacogenetics
  • VKORC1
  • Warfarin

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

Cite this

Responsiveness to low-dose warfarin associated with genetic variants of VKORC1, CYP2C9, CYP2C19, and CYP4F2 in an Indonesian population. / Rusdiana, T.; Araki, T.; Nakamura, Tomonori; Subarnas, A.; Yamamoto, K.

In: European Journal of Clinical Pharmacology, Vol. 69, No. 3, 03.2013, p. 395-405.

Research output: Contribution to journalArticle

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abstract = "Purpose: The aim of this study was to assess the pharmacokinetics and pharmacodynamics of warfarin associated with genetic polymorphisms in VKORC1, CYP2C9, CYP2C19, and CYP4F2 in Indonesian patients treated with low-dose warfarin. Methods: Genotyping of VKORC1, CYP2C9, CYP2C19, and CYP4F2 was carried out in 103 patients treated with a daily dose of 1-2 mg warfarin, 89 of whom were treated with a fixed daily dose of warfarin (1 mg). The plasma concentrations of S- and R-warfarin and S- and R-7-hydroxywarfarin were used as pharmacokinetic indices, while prothrombin time expressed as the international normalized ratio (PT-INR) was used as a pharmacodynamic index. Results: In patients treated with a fixed daily dose of warfarin (1 mg), a higher PT-INR was associated with VKORC1-1639 AA [median 1.35; interquartile range (IQR) 1.21-1.50] than with the GA (1.18; IQR 1.12-1.32; p < 0.01) and GG (1.02; IQR = 1.02-1.06; p < 0.01) polymorphisms, and with CYP2C9*1/*3 (1.63; IQR 1.45-1.85) compared to*1/*1 (1.23; IQR 1.13-1.43; p < 0.05). The S-warfarin concentration was significantly higher in patients with CYP2C9*1/*3 than in those with*1/*1 (p < 0.05). With low-dose warfarin administration, there was no significant difference in the concentrations of warfarin metabolites among any of the genotype variants. The genotype variations of CYP2C19 and CYP4F2 were not significantly associated with the PT-INR. Conclusion: For low-dose warfarin treatment, the VKORC1-1639 G > A and CYP2C9 genotype variations affected the pharmacokinetics and pharmacodynamics of warfarin, while we could not find significant effects of CYP4F2 or CYP2C19 genotype variations on warfarin (metabolite) concentrations or PT-INR.",
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T1 - Responsiveness to low-dose warfarin associated with genetic variants of VKORC1, CYP2C9, CYP2C19, and CYP4F2 in an Indonesian population

AU - Rusdiana, T.

AU - Araki, T.

AU - Nakamura, Tomonori

AU - Subarnas, A.

AU - Yamamoto, K.

PY - 2013/3

Y1 - 2013/3

N2 - Purpose: The aim of this study was to assess the pharmacokinetics and pharmacodynamics of warfarin associated with genetic polymorphisms in VKORC1, CYP2C9, CYP2C19, and CYP4F2 in Indonesian patients treated with low-dose warfarin. Methods: Genotyping of VKORC1, CYP2C9, CYP2C19, and CYP4F2 was carried out in 103 patients treated with a daily dose of 1-2 mg warfarin, 89 of whom were treated with a fixed daily dose of warfarin (1 mg). The plasma concentrations of S- and R-warfarin and S- and R-7-hydroxywarfarin were used as pharmacokinetic indices, while prothrombin time expressed as the international normalized ratio (PT-INR) was used as a pharmacodynamic index. Results: In patients treated with a fixed daily dose of warfarin (1 mg), a higher PT-INR was associated with VKORC1-1639 AA [median 1.35; interquartile range (IQR) 1.21-1.50] than with the GA (1.18; IQR 1.12-1.32; p < 0.01) and GG (1.02; IQR = 1.02-1.06; p < 0.01) polymorphisms, and with CYP2C9*1/*3 (1.63; IQR 1.45-1.85) compared to*1/*1 (1.23; IQR 1.13-1.43; p < 0.05). The S-warfarin concentration was significantly higher in patients with CYP2C9*1/*3 than in those with*1/*1 (p < 0.05). With low-dose warfarin administration, there was no significant difference in the concentrations of warfarin metabolites among any of the genotype variants. The genotype variations of CYP2C19 and CYP4F2 were not significantly associated with the PT-INR. Conclusion: For low-dose warfarin treatment, the VKORC1-1639 G > A and CYP2C9 genotype variations affected the pharmacokinetics and pharmacodynamics of warfarin, while we could not find significant effects of CYP4F2 or CYP2C19 genotype variations on warfarin (metabolite) concentrations or PT-INR.

AB - Purpose: The aim of this study was to assess the pharmacokinetics and pharmacodynamics of warfarin associated with genetic polymorphisms in VKORC1, CYP2C9, CYP2C19, and CYP4F2 in Indonesian patients treated with low-dose warfarin. Methods: Genotyping of VKORC1, CYP2C9, CYP2C19, and CYP4F2 was carried out in 103 patients treated with a daily dose of 1-2 mg warfarin, 89 of whom were treated with a fixed daily dose of warfarin (1 mg). The plasma concentrations of S- and R-warfarin and S- and R-7-hydroxywarfarin were used as pharmacokinetic indices, while prothrombin time expressed as the international normalized ratio (PT-INR) was used as a pharmacodynamic index. Results: In patients treated with a fixed daily dose of warfarin (1 mg), a higher PT-INR was associated with VKORC1-1639 AA [median 1.35; interquartile range (IQR) 1.21-1.50] than with the GA (1.18; IQR 1.12-1.32; p < 0.01) and GG (1.02; IQR = 1.02-1.06; p < 0.01) polymorphisms, and with CYP2C9*1/*3 (1.63; IQR 1.45-1.85) compared to*1/*1 (1.23; IQR 1.13-1.43; p < 0.05). The S-warfarin concentration was significantly higher in patients with CYP2C9*1/*3 than in those with*1/*1 (p < 0.05). With low-dose warfarin administration, there was no significant difference in the concentrations of warfarin metabolites among any of the genotype variants. The genotype variations of CYP2C19 and CYP4F2 were not significantly associated with the PT-INR. Conclusion: For low-dose warfarin treatment, the VKORC1-1639 G > A and CYP2C9 genotype variations affected the pharmacokinetics and pharmacodynamics of warfarin, while we could not find significant effects of CYP4F2 or CYP2C19 genotype variations on warfarin (metabolite) concentrations or PT-INR.

KW - CYP2C9

KW - CYP4F2

KW - Pharmacogenetics

KW - VKORC1

KW - Warfarin

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JO - European Journal of Clinical Pharmacology

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