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Metabolism of warfarin enantiomers in Japanese patients with heart disease having different CYP2C9 and CYP2C19 genotypes
Author(s) -
Takahashi Harumi,
Kashima Toshitaka,
Nomizo Yuko,
Muramoto Nagisa,
Shimizu Teppei,
Nasu Kayoko,
Kubota Takahiro,
Kimura Sosuke,
Echizen Hirotoshi
Publication year - 1998
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(98)90103-5
Subject(s) - cyp2c9 , cyp2c19 , warfarin , pharmacogenetics , pharmacology , chemistry , hydroxylation , pharmacokinetics , genotype , medicine , endocrinology , metabolism , cytochrome p450 , biochemistry , atrial fibrillation , enzyme , gene
Objective To determine whether genetic polymorphism of cytochrome P450 (CYP) 2C9 or 2C19 affects the in vivo metabolism of warfarin enantiomers. Methods Eighty‐six Japanese patients heart disease who were given warfarin participated in the study. Plasma unbound concentrations of warfarin enantiomers and urinary ( S )‐7‐hydroxywarfarin concentrations were measured by means of a chiral HPLC and ultrafiltration technique to calculate the unbound oral clearance (CL po,u ) for the enantiomers and the formation clearance (CL m ) for ( S )‐warfarin 7‐hydroxylation. Genotyping for CYP2C9 (the wild type [wt], Arg 144 Cys, and Ile 359 Leu) and for CYP2C19 (wt, m1, and m2) was performed with a polymerase chain reaction method. Results Three patients were heterozygous for the CYP2C9 Leu 359 mutation but none were homozygous for the mutation (the allele frequency of 0.017). None had a CYP2C9 Cys 144 allele. The medians for ( S )‐warfarin CL po,u and its 7‐hydroxylation CL m obtained from heterozygotes of CYP2C9 Leu 359 were significantly less than those obtained from homozygotes of the wt allele, as follows: 234 ml/min (range, 156 to 269 ml/min) versus 632 ml/min (range, 180 to 2070 ml/min) ( p < 0.001) and 0.20 ml/min (range, 0.05 to 0.77 ml/min) versus 0.80 ml/min (range, 0.05 to 14.9 ml/min) ( p < 0.05), respectively. In contrast, no difference was observed in ( R )‐warfarin CL po,u between the groups. The allele frequencies for CYP2C19 m1 and CYP2C19 m2 were 0.26 and 0.14, respectively, indicating 15% of patients were genotypically poor metabolizers of CYP2C19 . No difference in CL po,u for warfarin enantiomers was observed between the assumed CYP2C19 phenotypes. Conclusion Heterozygotes for CYP2C9 Ile 359 /Leu allele have reduced in vivo metabolism of ( S )‐warfarin but not ( R )‐warfarin. Because ( S )‐warfarin has a greater anticoagulant potency than its ( R )‐congener, the genetic polymorphism of CYP2C9 may partly account for the large interpatient variability in therapeutic dosages of warfarin. Clinical Pharmacology & Therapeutics (1998) 63 , 519–528; doi: