CYP2C8 is a cytochrome P450 monooxygenase localized to the endoplasmic reticulum that catalyzes the oxidative metabolism of both endogenous and exogenous substrates 1. Mechanistically, the enzyme uses molecular oxygen to insert one atom into substrates while reducing the second to water, with electrons supplied by NADPH via cytochrome P450 reductase 1. CYP2C8 primarily catalyzes epoxidation of polyunsaturated fatty acid double bonds, hydroxylation of steroid hormones (particularly 16-alpha-hydroxylation of 17beta-estradiol and estrone), retinoic acid 4-hydroxylation, and metabolism of arachidonic acid 1. The enzyme's large, trifurcated active site cavity enables metabolism of more than 60 clinical drugs, making it a major catalyst in biotransformation of paclitaxel, amodiaquine, troglitazone, amiodarone, verapamil, and ibuprofen 1. Clinically, CYP2C8 genetic polymorphisms significantly influence drug efficacy and adverse effects. Variant alleles (rs1058932, rs2275622) are associated with increased hypertensive intracerebral hemorrhage risk in Han Chinese populations 2. CYP2C8 polymorphisms affect antimalarial amodiaquine efficacy, with low-metabolizer genotypes found in 1-4% of African populations 3. Genetic variations also influence repaglinide and tucatinib pharmacokinetics; CYP2C8 *3 carriers exhibit significantly reduced drug exposure 4 5. Strong CYP2C8 inhibitors like gemfibrozil cause clinically meaningful drug-drug interactions through mechanism-based inhibition 6. Factors affecting interaction magnitude include genetic polymorphisms, hepatic function, drug properties, and metabolite inhibitory potency 7.