CYP2C8-Mediated Drug-Drug Interactions and the Factors Influencing the Interaction Magnitude.

IF 5.1 2区医学 Q1 CHEMISTRY, MEDICINAL

Drug Design, Development and Therapy Pub Date : 2025-09-16 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S541536

Ling-Ling Zhu, Ling-Yan Yu, Yan-Hong Wang, Quan Zhou

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引用次数: 0

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

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cyp2c8介导的药物相互作用及影响相互作用程度的因素。

背景：老年人经常有多种疾病，可能导致多重用药。细胞色素P450 (CYP) 2C8在多种药物代谢中有重要作用；然而，与主要的CYP酶（如CYP3A4， CYP2D6）相比，其相关的药物-药物相互作用（ddi）在临床实践中似乎未被充分认识。本文就cyp2c8介导ddi的研究进展及影响相互作用程度的因素进行综述。方法：以CYP2C8和药物相互作用为检索词，检索截至2025年1月的PubMed、Web of Science和Embase文献。根据PRISMA指南确定了符合条件的研究。筛选和纳入由两名独立评论者评估，57项研究符合纳入/排除标准。结果：基于权威来源（FDA， EMA, DrugBank）和文献，本综述确定了CYP2C8的5种诱导剂，53种强/中度抑制剂和32种主要/中间底物。并举例说明了用体内外推法预测ddi的典型例子。影响DDI大小的因素包括遗传多态性（CYP2C8、SLCO1B1、UDP-glucuronosyltransferase、pregnane X受体）、肝肾功能、CYP2C8施药者的性质（剂量、治疗过程、全身浓度、停药后时间、抑制效力、代谢物对CYP2C8的抑制能力）、目标药物的性质（目标药物的活性代谢物是否为CYP2C8底物、治疗指标、立体选择性）、相似治疗类别药物的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。结论：CYP2C8是一种重要但未被充分认识的二甲醚。本文综述了相互作用的主要基础、肇事者、ddi和预测相互作用的方法，并首次全面总结了影响相互作用大小的因素。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优先事项，将会出现进一步的进展。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.