Takahashi H, Echizen H
Department of Pharmacotherapy, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan.
Clin Pharmacokinet. 2001;40(8):587-603. doi: 10.2165/00003088-200140080-00003.
Warfarin is one of the most widely prescribed oral anticoagulants. However, optimal use of the drug has been hampered by its >10-fold interpatient variability in the doses required to attain therapeutic responses. Pharmacogenetic polymorphism of cytochrome P450 (CYP) may be associated with impaired elimination of warfarin and exaggerated anticoagulatory responses to the drug in certain patients. Clinically available warfarin is a racemic mixture of (R)- and (S)-warfarin, and the (S)-enantiomer has 3 to 5 times greater anticoagulation potency than its optical congener. Both enantiomers are eliminated extensively via hepatic metabolism with low clearance relative to hepatic blood flow. CYP2C9 is almost exclusively responsible for the metabolism of the pharmacologically more active (S)-enantiomer. Several human allelic variants of CYP2C9 have been cloned, designated as CYP2C91 (reference sequence or wild-type allele), CYP2C92, CYP2C93 and CYP2C94, respectively. The allelic frequencies for these variants differ considerably among different ethnic populations. Caucasians appear to carry the CYP 2C92 (8 to 20%) and CYP2C93 (6 to 10%) variants more frequently than do Asians (0% and 2 to 5%, respectively). The metabolic activities of the CYP2C9 variants have been investigated in vitro. The catalytic activity of CYP2C93 expressed from cDNA was significantly less than that of CYP2C91. Human liver microsomes obtained from individuals heterozygous for CYP2C93 showed significantly reduced (S)-warfarin 7-hydroxylation as compared with those obtained from individuals genotyped as CYP2C91. The influence of the CYP2C93 allele on the in vivo pharmacokinetics of (S)-warfarin has been studied in Japanese patients. Patients with the homozygous CYP2C93 genotype, as well as those with the heterozygous CYP2C91/3 genotype, had significantly reduced clearance of (S)-warfarin (by 90 and 60%, respectively) compared with those with homozygous CYP2C91. The maintenance dosages of warfarin required in Japanese patients with heterozygous and homozygous CYP2C93 mutations were significantly lower than those in patients with CYP2C91/1. In addition, 86% of British patients exhibiting adequate therapeutic responses with lower maintenance dosages of warfarin (<1.5 mg/day) had either the CYP2C92 or CYP2C93 mutation singly or in combination, whereas only 38% of randomly selected patients receiving warfarin carried the corresponding mutations. Furthermore, the former group showed more frequent episodes of major bleeding associated with warfarin therapy. These data indicate that the CYP2C9*3 allele may be associated with retarded elimination of (S)-warfarin and the resulting clinical effects. However, relationships between CYP2C9 genotype, enzyme activity, metabolism of probe substrates, dosage requirements and bleeding complications should be interpreted with caution, and further studies are required.
华法林是最常用的口服抗凝剂之一。然而，由于达到治疗反应所需剂量在患者间存在10倍以上的差异，该药的最佳使用受到了阻碍。细胞色素P450（CYP）的药物遗传多态性可能与华法林消除受损以及某些患者对该药的抗凝反应增强有关。临床使用的华法林是（R）-和（S）-华法林的外消旋混合物，（S）-对映体的抗凝效力是其旋光异构体的3至5倍。两种对映体都主要通过肝脏代谢消除，相对于肝血流量清除率较低。CYP2C9几乎专门负责药理活性更强的（S）-对映体的代谢。已克隆出CYP2C9的几种人类等位基因变体，分别命名为CYP2C91（参考序列或野生型等位基因）、CYP2C92、CYP2C93和CYP2C94。这些变体的等位基因频率在不同种族人群中差异很大。与亚洲人（分别为0%和2%至5%）相比，高加索人似乎更频繁地携带CYP 2C92（8%至20%）和CYP2C93（6%至10%）变体。已在体外研究了CYP2C9变体的代谢活性。从cDNA表达的CYP2C93的催化活性明显低于CYP2C91。与基因型为CYP2C91的个体相比，从CYP2C93杂合个体获得的人肝微粒体显示（S）-华法林7-羟化明显降低。在日本患者中研究了CYP2C93等位基因对（S）-华法林体内药代动力学的影响。与纯合CYP2C91患者相比，纯合CYP2C93基因型患者以及杂合CYP2C91/3基因型患者的（S）-华法林清除率明显降低（分别降低90%和60%）。日本携带杂合和纯合CYP2C93突变患者所需的华法林维持剂量明显低于CYP2C91/1患者。此外，86%对华法林维持剂量较低（<1.5mg/天）有充分治疗反应的英国患者单独或联合携带CYP2C92或CYP2C93突变，而随机选择接受华法林治疗的患者中只有38%携带相应突变。此外，前一组患者华法林治疗相关的大出血发作更频繁。这些数据表明CYP2C9*3等位基因可能与（S）-华法林消除延迟及由此产生的临床效应有关。然而，应谨慎解释CYP2C9基因型、酶活性、探针底物代谢、剂量需求和出血并发症之间的关系，还需要进一步研究。
