Kusama Makiko, Maeda Kazuya, Chiba Koji, Aoyama Akinori, Sugiyama Yuichi
Laboratory of Pharmaceutical Regulatory Science, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Pharm Res. 2009 Apr;26(4):822-35. doi: 10.1007/s11095-008-9781-2. Epub 2008 Dec 12.
The *2 and *3 alleles of CYP2C9, with decreased enzymatic activity, are highly polymorphic and contribute to inter-individual differences in pharmacotherapy of CYP2C9 substrates. Here, we sought for a simplified theoretical method to predict the pharmacokinetic changes with minimal in vivo data.
The changes in clearances of CYP2C9 substrates in subjects with these alleles were quantitatively estimated by parameters from literature data: intrinsic metabolic clearance and the enzyme expression level of mutated CYP2C9, contribution of CYP2C9 to the CYP-mediated clearance (f (m2C9)), and the contribution of the dominant metabolic pathways to the total clearance (f (h)). To validate the accuracy of our prediction, the changes were compared to reported in vivo values.
Sufficient data were available for nine substrates: celecoxib, diclofenac, S-flurbiprofen, losartan, S-phenprocoumon, phenytoin, tolbutamide, torsemide, and S-warfarin. These predicted values, either using the intrinsic clearance specific to each substrate, or the averaged values (*2: 0.66, *3: 0.13, (ratio to *1)), correlated well with observed values (r (2) = 0.812, 0.786, respectively).
This theoretical method well estimated the quantitative changes in pharmacokinetics of CYP2C9 substrates in subjects with mutated alleles of CYP2C9. This can be applied to drug development even from the early clinical phases.
细胞色素P450 2C9（CYP2C9）的2和3等位基因具有降低的酶活性，高度多态性，并导致CYP2C9底物药物治疗中的个体差异。在此，我们寻求一种简化的理论方法，以用最少的体内数据预测药代动力学变化。
通过文献数据中的参数定量估计具有这些等位基因的受试者中CYP2C9底物清除率的变化：内在代谢清除率和突变型CYP2C9的酶表达水平、CYP2C9对CYP介导的清除率的贡献（f（m2C9））以及主要代谢途径对总清除率的贡献（f（h））。为验证我们预测的准确性，将这些变化与已报道的体内值进行比较。
有九种底物有足够的数据：塞来昔布、双氯芬酸、S-氟比洛芬、氯沙坦、S-苯丙香豆素、苯妥英、甲苯磺丁脲、托拉塞米和S-华法林。这些预测值，无论是使用每种底物特有的内在清除率，还是平均值（*2：0.66，3：0.13，相对于1的比率），均与观察值具有良好的相关性（r（2）分别为0.812、0.786）。
这种理论方法很好地估计了具有CYP2C9突变等位基因的受试者中CYP2C9底物药代动力学的定量变化。这甚至可从临床早期阶段应用于药物开发。
