Shimamoto J, Ieiri I, Urae A, Kimura M, Irie S, Kubota T, Chiba K, Ishizaki T, Otsubo K, Higuchi S
Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Eur J Clin Pharmacol. 2000 Apr;56(1):65-8. doi: 10.1007/s002280050722.
Evidence exists to suggest that diclofenac is metabolised by CYP2C9. The present study was undertaken in order to evaluate the effect of the single CYP2C9*3 variant on drug metabolism using diclofenac as a probe drug.
A single dose of diclofenac was administered orally to 12 healthy subjects in whom the genotype of CYP2C9 had been determined previously. The disposition kinetics of diclofenac were compared between homozygotes for the wild type (CYP2C9*1/1, n = 6) and heterozygotes for the Leu359 variant (CYP2C91/*3, n = 6).
For diclofenac, the following kinetic parameters were observed in the CYP2C9*1/1 and CYP2C91/3 subjects, respectively (mean +/- SD): apparent oral clearance (ml/kg/h) 355.8 +/- 56.9 and 484.4 +/- 155.3; area under plasma concentration time curve (microg h/ml) 2.7 +/- 0.7 and 1.9 +/- 0.6. The formation clearance of 4'-hydroxydiclofenac (ml/kg/h) was 63.6 +/- 19.1 in the CYP2C91/1 subjects compared with 75.9 +/- 27.6 in the CYP2C91/*3 subjects. There were no significant differences in any of the kinetic parameters for either diclofenac disposition or formation clearance of 4'-hydroxydiclofenac between the two genotype groups.
Since the disposition kinetics of diclofenac does not change in subjects with the single CYP2C9*3 mutant allele, it is suggested that the effects of CYP2C9 polymorphisms on the drug metabolism tend to be substrate specific.
有证据表明双氯芬酸由细胞色素P450 2C9（CYP2C9）代谢。本研究旨在以双氯芬酸作为探针药物，评估单个CYP2C9*3变体对药物代谢的影响。
对12名先前已确定CYP2C9基因型的健康受试者口服单剂量双氯芬酸。比较野生型纯合子（CYP2C9*1/1，n = 6）和亮氨酸359变体杂合子（CYP2C91/*3，n = 6）之间双氯芬酸的处置动力学。
对于双氯芬酸，在CYP2C9*1/1和CYP2C91/3受试者中分别观察到以下动力学参数（平均值±标准差）：表观口服清除率（ml/kg/h）为355.8±56.9和484.4±155.3；血浆浓度-时间曲线下面积（μg h/ml）为2.7±0.7和1.9±0.6。CYP2C91/1受试者中4'-羟基双氯芬酸的生成清除率（ml/kg/h）为63.6±19.1，而CYP2C91/*3受试者中为75.9±27.6。两个基因型组之间双氯芬酸处置或4'-羟基双氯芬酸生成清除率的任何动力学参数均无显著差异。
由于具有单个CYP2C9*3突变等位基因的受试者中双氯芬酸的处置动力学没有变化，因此表明CYP2C9多态性对药物代谢的影响往往具有底物特异性。
