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

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.