Rodrigues A David
Bristol-Myers Squibb, Pharmaceutical Research Institute, Mailstop F14-04, P.O. Box 4000, Princeton, NJ 08543, USA.
Drug Metab Lett. 2007 Jan;1(1):31-5. doi: 10.2174/187231207779814247.
For any new chemical entity (NCE), in vitro inhibition constants (K(i)) for the different human cytochrome P450 (CYP) forms can be ranked (lowest to highest). The CYP form with the lowest in vitro K(i) is evaluated first clinically, employing a suitable probe drug like midazolam (CYP3A4), theophylline (CYP1A2), (S)-warfarin (CYP2C9) and desipramine (CYP2D6), and the NCE is classified as a "none", "weak", "moderate", or "strong" inhibitor. In turn, the classification governs the next steps. A two stage strategy, in vitro ranking followed by classification, has the potential to enable decision making within an industrial and regulatory setting. With additional refinement and validation, the approach could be applied to mechanism-based inhibitors, inducers and substrates of CYPs also.
对于任何新化学实体（NCE），不同人类细胞色素P450（CYP）形式的体外抑制常数（K(i)）可以进行排序（从最低到最高）。首先对体外K(i)最低的CYP形式进行临床评估，使用合适的探针药物，如咪达唑仑（CYP3A4）、茶碱（CYP1A2）、（S）-华法林（CYP2C9）和地昔帕明（CYP2D6），然后将NCE分类为“无”、“弱”、“中”或“强”抑制剂。相应地，该分类决定后续步骤。体外排序后再分类的两阶段策略，有可能在工业和监管环境中实现决策制定。经过进一步完善和验证后，该方法也可应用于基于机制的CYP抑制剂、诱导剂和底物。
