Cytochrome P450 family 2 subfamily C member 8 (CYP2C8) (CYP2C8)

Cytochrome P450 2C8 (CYP2C8) is a critical phase I drug-metabolizing enzyme primarily expressed in the liver (UniProt: P10632). It belongs to the cytochrome P450 superfamily and is responsible for the oxidative metabolism of approximately 5% of clinically used drugs, including paclitaxel, amodiaquine, and various glitazones (PubMed: 21174620). In the context of pulmonary arterial hypertension treatment, CYP2C8 is the major enzyme responsible for the metabolism of ACT-333679, the potent active metabolite of the prodrug selexipag (FDA: Uptravi Label). The clinical scenario of concomitant exposure with rifampicin is significant because rifampicin is a potent inducer of CYP2C8 expression via the pregnane X receptor (PXR). This induction leads to a dramatic increase in the metabolic clearance of ACT-333679, resulting in a roughly 80% decrease in its systemic exposure (AUC), which can render selexipag therapy ineffective (DrugBank: DB09103). Consequently, CYP2C8 is a major site of drug-drug interactions that must be carefully managed to ensure patient safety and drug efficacy.

Other names

CYPIIC8S-mephenytoin 4-hydroxylaseCytochrome P450 subfamily IIC polypeptide 8CP2C8

CYP2C8 catalyzes the oxidative metabolism of drugs and endogenous lipids; rifampicin induces its expression via PXR activation, while selexipag's active metabolite is a primary substrate.