Zhu Ling-Ling, Yu Ling-Yan, Wang Yan-Hong, Zhou Quan
VIP Care and Geriatric Ward, Division of Nursing, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China.
Department of Pharmacy, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China.
Drug Des Devel Ther. 2025 Sep 16;19:8391-8413. doi: 10.2147/DDDT.S541536. eCollection 2025.
Older adults often have multiple morbidities that may lead to polypharmacy. Cytochrome P450 (CYP) 2C8 has shown significant contributions in the metabolism of various medications; however, its related drug-drug interactions (DDIs) appear to be underrecognized in clinical practice compared to the major CYP enzymes (eg, CYP3A4, CYP2D6). This review summarizes the progress of CYP2C8-mediated DDIs and factors influencing the interaction magnitude.
Using CYP2C8 and drug interactions as the search terms, literature was searched through PubMed, Web of Science, and Embase as of January 2025. Eligible studies were identified following PRISMA guidelines. Screening and inclusion were assessed by two independent reviewers and 57 studies met inclusion/exclusion criteria.
Based on authoritative sources (FDA, EMA, DrugBank), and literature, this review identified 5 inducers, 53 strong/moderate inhibitors, and 32 major/intermediate substrates of CYP2C8. Typical examples were illustrated to predict DDIs by in vitro-in vivo extrapolation. The factors influencing DDI magnitude include genetic polymorphisms (CYP2C8, SLCO1B1, UDP-glucuronosyltransferase, and pregnane X receptor), hepatic and renal function, properties of CYP2C8 perpetrators (dose, treatment course, systemic concentrations, time after discontinuation, inhibitory potency, inhibitory abilities of metabolites on CYP2C8), properties of object drugs (whether the active metabolite of object drug is a CYP2C8 substrate, therapeutic index, stereoselectivity), differences in DDI risk for drugs from similar therapeutic classes, and whether multiple interaction mechanisms are involved. Some botanical supplements showed potential to influence CYP2C8 in vitro or in animal experiments.
CYP2C8 is an important but underrecognized DME. This article reviewed its main substrates, perpetrators, DDIs, and methods for predicting interactions, and provided the first comprehensive summary of the factors influencing the interaction magnitude. Such knowledge will enhance the awareness of clinical professionals regarding safe medication for older adults. Further advances will emerge if the gaps in current knowledge and priorities for future research are recognized.
老年人常患有多种疾病，可能导致多重用药。细胞色素P450（CYP）2C8在多种药物的代谢中发挥了重要作用；然而，与主要的CYP酶（如CYP3A4、CYP2D6）相比，其相关的药物相互作用（DDIs）在临床实践中似乎未得到充分认识。本综述总结了CYP2C8介导的DDIs的进展以及影响相互作用程度的因素。
以CYP2C8和药物相互作用为检索词，截至2025年1月通过PubMed、Web of Science和Embase进行文献检索。按照PRISMA指南确定符合条件的研究。由两名独立审阅者进行筛选和纳入评估，57项研究符合纳入/排除标准。
基于权威来源（FDA、EMA、DrugBank）及文献，本综述确定了5种诱导剂、53种强/中度抑制剂以及32种CYP2C8的主要/中间底物。通过体外-体内外推法举例说明了预测DDIs的典型例子。影响DDI程度的因素包括基因多态性（CYP2C8、SLCO1B1、尿苷二磷酸葡萄糖醛酸转移酶和孕烷X受体）、肝肾功能、CYP2C8肇事者的特性（剂量、疗程、全身浓度、停药后时间、抑制效力、代谢物对CYP2C8的抑制能力）、目标药物的特性（目标药物的活性代谢物是否为CYP2C8底物、治疗指数、立体选择性）、来自相似治疗类别的药物的DDI风险差异以及是否涉及多种相互作用机制。一些植物补充剂在体外或动物实验中显示出影响CYP2C8的潜力。
CYP2C8是一种重要但未得到充分认识的药物代谢酶。本文综述了其主要底物、肇事者、DDIs以及预测相互作用的方法，并首次全面总结了影响相互作用程度的因素。这些知识将提高临床专业人员对老年人安全用药的认识。如果认识到当前知识的差距和未来研究的重点，将会取得进一步进展。
