Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Higashi-Tamagawa Gakuen, Machida, Tokyo, Japan.
Curr Drug Metab. 2011 Jul;12(6):549-69. doi: 10.2174/138920011795713724.
This review focuses on stereoselectivity of human cytochrome P450 (P450 or CYP) in the area of metabolism and inhibition. A meta-analysis was performed based on the reported values regarding (1) values of the Michaelis-Menten constant (K(m)), maximal velocity (V(max)), and intrinsic clearance (V(max)/K(m)) for 45 metabolic reactions of 19 substrates and (2) inhibition constants (K(i)) for 6 inhibitors. The median (R)/(S)-enantiomer ratios of the K(m), V(max), and V(max)/K(m) values for CYP1A2, CYP2B6, CYP2C19, CYP2D6, and CYP3A4 were in the range of 0.80-1.53, whereas the median ratios of V(max), and V(max)/K(m) values for CYP2C9 were 0.43 and 0.60, respectively. In addition, the parameters for metabolic reactions (25-80%) of (R)-enantiomers of these P450s were comparable to those of (S)-enantiomers (the ratios were between 0.5 and 2), whereas 45-69% of V(max) and V(max)/K(m) values for the (R)-enantiomer in CYP2C9 were less than half of those for the (S)-enantiomer, although the kinetic behavior of the stereoselectivity depended on the metabolic reaction. There is a limited number of reports regarding stereoselective inhibition and induction in vitro. The present information gives insight into the contribution of stereoselectivity to metabolism mediated by P450s and the risk of adverse drug-drug interactions due to stereoselectivity.
这篇综述聚焦于人类细胞色素 P450（P450 或 CYP）在代谢和抑制方面的立体选择性。基于已报道的 19 种底物的 45 种代谢反应的米氏常数（K(m)）、最大速度（V(max)）和内在清除率（V(max)/K(m)）值以及 6 种抑制剂的抑制常数（K(i)）值，进行了荟萃分析。CYP1A2、CYP2B6、CYP2C19、CYP2D6 和 CYP3A4 的 K(m)、V(max)和 V(max)/K(m)值的（R)/(S）-对映体比值中位数范围为 0.80-1.53，而 CYP2C9 的 V(max)和 V(max)/K(m)值的中位数比值分别为 0.43 和 0.60。此外，这些 P450 代谢反应（25-80%）的（R）-对映体参数与（S）-对映体相当（比值在 0.5 到 2 之间），而 CYP2C9 的（R）-对映体的 45-69%的 V(max)和 V(max)/K(m)值不到（S）-对映体的一半，尽管立体选择性的动力学行为取决于代谢反应。关于体外立体选择性抑制和诱导的报道数量有限。目前的信息深入了解了立体选择性对 P450 介导的代谢的贡献以及由于立体选择性导致的药物相互作用不良反应的风险。
