Department of Pharmacology and Pharmacy, Antoni van Leeuwenhoek/The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Division of Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Eur J Drug Metab Pharmacokinet. 2024 Jul;49(4):407-418. doi: 10.1007/s13318-024-00896-2. Epub 2024 Apr 30.
Cytochrome P450 (CYP) enzymes play a central role in the elimination of approximately 80% of all clinically used drugs. Differences in CYP enzyme activity between individuals can contribute to interindividual variability in exposure and, therefore, treatment outcome. In vivo CYP enzyme activity could be determined with phenotyping. Currently, (sub)therapeutic doses are used for in vivo phenotyping, which can lead to side effects. The use of microdoses (100 µg) for in vivo phenotyping for CYP enzymes could overcome the limitations associated with the use of (sub)therapeutic doses of substrates. The aim of this review is to provide a critical overview of the application of microdosing for in vivo phenotyping of CYP enzymes. A literature search was performed to find drug-drug interaction studies of CYP enzyme substrates that used microdoses of the respective substrates. A substrate was deemed sensitive to changes in CYP enzyme activity when the pharmacokinetics of the substrate significantly changed during inhibition and induction of the enzyme. On the basis of the currently available evidence, the use of microdosing for in vivo phenotyping for subtypes CYP1A2, CYP2C9, CYP2D6, and CYP2E1 is not recommended. Microdosing can be used for the in vivo phenotyping of CYP2C19 and CYP3A. The recommended microdose phenotyping test for CYP2C19 is measuring the omeprazole area-under-the-concentration-time curve over 24 h (AUC) after administration of a single 100 µg dose. CYP3A activity could be best determined with a 0.1-75 µg dose of midazolam, and subsequently measuring AUC extrapolated to infinity (AUC) or clearance. Moreover, there are two metrics available for midazolam using a limited sampling strategy: AUC over 10 h (AUC) and AUC from 2 to 4 h (AUC).
细胞色素 P450（CYP）酶在消除约 80%的所有临床应用药物中起着核心作用。个体之间 CYP 酶活性的差异可能导致暴露的个体间变异性，因此治疗结果也会有所不同。CYP 酶活性可以通过表型测定来确定。目前，（亚）治疗剂量用于体内表型测定，但可能会导致副作用。使用微剂量（100μg）进行 CYP 酶的体内表型测定可以克服与使用（亚）治疗剂量底物相关的限制。本综述的目的是批判性地概述微剂量在 CYP 酶体内表型测定中的应用。进行了文献检索，以查找使用各自底物的微剂量进行 CYP 酶底物药物-药物相互作用研究。当底物的药代动力学在酶的抑制和诱导过程中显著改变时，该底物被认为对 CYP 酶活性的变化敏感。根据目前的证据，不建议将微剂量用于 CYP1A2、CYP2C9、CYP2D6 和 CYP2E1 亚型的体内表型测定。微剂量可用于 CYP2C19 和 CYP3A 的体内表型测定。推荐的 CYP2C19 微剂量表型测定试验是在单次给予 100μg 剂量后测量奥美拉唑 24 小时浓度-时间曲线下面积（AUC）。CYP3A 活性可以用咪达唑仑的 0.1-75μg 剂量最佳确定，随后测量外推至无穷大的 AUC（AUC）或清除率。此外，使用有限采样策略，有两种用于咪达唑仑的指标：10 小时 AUC（AUC）和 2 至 4 小时 AUC（AUC）。
