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Excerpt
Anticoagulant therapy is known by its inter-individual differences in daily dose requirement for a given target level of anticoagulation (International Normalized Ratio of prothrombin time). For acenocoumarol, the majority of patients require 2–4 mg daily. There are, however, patients requiring 1 mg or less, while others require much higher doses. Variations in pharmacodynamics may underlie the individual differences. In a survey of donor human livers only minor, two to three-fold, differences were found in the biochemical activities of the hepatic vitamin K-dependent systems (Thijssen & Drittij-Reijnders, 1993). Alternatively, the inter-individual differences in sensitivity may be due to variations in pharmacokinetics. The elimination of acenocoumarol is almost exclusively by biotransformation, mainly 6- and 7-hydroxylation of the coumarin part of the molecules. The main cytochrome P450 enzymes involved are CYP2C9 [6- and 7-hydroxylations of (S)-acenocoumarol, 7-hydroxylation of (R)-acenocoumarol] and CYP2C19 [6- and 7-hydroxylation of (R)-acenocoumarol] (Hermans & Thijssen, 1993;Thijssen et al., submitted). CYP2C9 is also the main enzyme catalysing the 7-hydroxylation of (S)-warfarin (Kaminsky & Zhang, 1997).
Genetic polymorphism is known for both enzymes, CYP2C9 and CYP2C19. Of the various CYP2C9 mutants, the variants CYP2C9*2 (Cys144/Ile359) and CYP2C9*3 (Arg144/Leu359) have been reported with altered catalytic activities compared to the wild-type CYP2C9*1 (Arg144/Ile359). Generally, the Ile359 to Leu (CYP2C9*3) substitution leads to reduced intrinsic activity (Vmax/ Km) for various substrates, e.g. 80–90% reduced activity for the 7-hydroxylation of (S)-warfarin has been observed for the cDNA-expressed CYP2C9*3 enzyme (Sullivan-Klose et al., 1996;Takahashi et al., 1998a;Yamazaki et al., 1998). The effect of the Arg144 to cystein substitution (CYP2C9*2) is less clear, no change (Sullivan-Klose et al., 1996) or reduced activity (Rettie et al., 1994) in (S)-warfarin hydroxylation has been reported. The CYP2C9 variants have been associated with enhanced sensitivity for warfarin. Furuya et al. (1995) reported significantly lower warfarin requirements in subjects carrying the CYP2C9*2 allele (all heterozygous). A subject homozygous for CYP2C9*3 was found to be extremely sensitive for warfarin, requiring not more than 0.5 mg of the racemic drug per day (Steward et al., 1997). Aithal et al. (1999) found carriers of either CYP2C9*2 and CYP2C9*3 to have reduced warfarin dose requirement and to be at higher risk of bleedings.
Genetic CYP2C19 polymorphism is due to defective alleles, termed CYP2C19*2, CYP2C19*3, and CYP2C19*4 (de Morais et al., 1994a, de Morais et al., 1994b;Ferguson et al., 1998). The phenotypes of CYP2C19 polymorphism are characterized as being extensive (homozygous and heterozygous for wild-type CYP2C19*1) and poor metabolizers of (S)-mephenytoin and other substrate drugs (de Morais et al., 1994a).
In this study, we investigated the genotypes of CYP2C9 and CYP2C19 in acenocoumarol anticoagulated patients and compared the allelic frequencies with the daily dose requirement. The study was approved by the Medical Ethical Committee of the Faculty of Medicine. All participants gave their written consent. Participants were recruited from patients attending the regional thrombosis service centre. Inclusion criteria were: age below 70 years, absence of heart-failure, stable anticoagulation for at least 3 months, and absence of comedication known to interfere (inhibition or induction of biotransformation) with oral anticoagulation. Three groups were formed in dependency of the daily acenocoumarol dose requirement: low-dose group L, requiring 1 mg or less; normal-dose group N, requiring 2–5 mg; and high-dose group H, requiring 7 mg or more.
