Kivistö K T, Kroemer H K
Department of Clinical Pharmacology, University of Helsinki, Finland.
J Clin Pharmacol. 1997 Jan;37(S1):40S-48S. doi: 10.1177/009127009703700121.
The pharmacokinetics of many drugs often vary considerably among individuals, largely because of variations in the expression of different cytochrome P-450 (CYP) enzymes in the liver and other tissues. Relatively selective substrate probes in vivo have been discovered for several major CYP isoforms involved in oxidative drug metabolism. Regarding isoforms that show genetic polymorphism (CYP2C19 and CYP2D6), genotyping as well as phenotyping with appropriate probe drugs can be used to distinguish between "poor" and "extensive" metabolizers. Measurement of CYP2D6 activity, which is being performed increasingly by means of genotyping, has an established role in the individualization of the dosage of selected CYP2D6 substrates. However, the therapeutic implications of extremely high CYP2D6 activity in some patients (ultrarapid metabolizers) need more attention. The therapeutic consequences of CYP2C19 polymorphism are not as well characterized as those of CYP2D6 polymorphism, but are likely to be of little significance with most CYP2C19 substrates. Probe-based assays are also available for measurement of in vivo activity of CYP1A2, CYP2E1 and CYP3A4; those will be discussed in detail in this review. These tests can be used, for example, to compare the activity of a specific isoform among patients and to characterize effects of such environmental factors as drugs and compounds in the diet on enzyme activity. However, it should be recognized that attempts to develop valid probe-based assays of in vivo activity of specific, nonpolymorphic CYP isoforms have proved relatively difficult; for example, none of the several putative probes of CYP3A4, the most important drug-metabolizing CYP isoform, is completely satisfactory. It is now clear that many diverse factors must be considered in the validation of these tests.
许多药物的药代动力学在个体之间往往有很大差异，这主要是由于肝脏和其他组织中不同细胞色素P-450（CYP）酶表达的差异。已经发现了几种参与氧化药物代谢的主要CYP亚型的相对选择性体内底物探针。对于表现出基因多态性的亚型（CYP2C19和CYP2D6），基因分型以及使用适当的探针药物进行表型分析可用于区分“慢”代谢者和“快”代谢者。通过基因分型越来越多地进行的CYP2D6活性测定，在选定的CYP2D6底物剂量个体化方面具有既定作用。然而，一些患者（超快代谢者）中极高的CYP2D6活性的治疗意义需要更多关注。CYP2C19多态性的治疗后果不如CYP2D6多态性那样明确，但对于大多数CYP2C19底物可能意义不大。基于探针的测定方法也可用于测量CYP1A2、CYP2E1和CYP3A4的体内活性；这些将在本综述中详细讨论。例如，这些测试可用于比较患者之间特定亚型的活性，并表征饮食中的药物和化合物等环境因素对酶活性的影响。然而，应该认识到，开发有效的基于探针的特定非多态性CYP亚型体内活性测定方法相对困难；例如，最重要的药物代谢CYP亚型CYP3A4的几种假定探针都不完全令人满意。现在很清楚，在这些测试的验证中必须考虑许多不同的因素。
