Cytochrome P450 3A and P-glycoprotein (CYP3A / P-gp)

Cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) are critical proteins involved in the absorption, distribution, metabolism, and excretion (ADME) of various drugs, including the S1P receptor modulator ozanimod. CYP3A4 is a major hepatic and intestinal enzyme that catalyzes the oxidative metabolism of many xenobiotics, while P-gp is an ATP-dependent efflux transporter that limits the intracellular accumulation of its substrates (UniProt P08684, P08183). In the case of ozanimod, while its primary metabolic pathway involves alcohol and aldehyde dehydrogenases, CYP3A4 contributes to secondary metabolic routes. Additionally, ozanimod is a substrate for P-gp-mediated transport (FDA Zeposia Label). The interaction between these proteins and ozanimod is clinically significant because potent inducers or inhibitors of CYP3A and P-gp can substantially alter the plasma concentrations of ozanimod and its active metabolites, CC-112273 and CC-1084037. For instance, co-administration with rifampin, a strong inducer, has been shown to decrease the exposure of these active metabolites by approximately 60%, which may lead to reduced clinical efficacy (Tran et al., 2020). Consequently, monitoring and managing these pharmacokinetic interactions is essential for maintaining the therapeutic window of ozanimod in patients with multiple sclerosis or ulcerative colitis.

Other names

CYP3A4ABCB1MDR1Cytochrome P450 3A4ATP-binding cassette sub-family B member 1Multidrug resistance protein 1

Ozanimod is a substrate for P-glycoprotein (P-gp) efflux and undergoes minor metabolism via Cytochrome P450 3A4 (CYP3A4). The primary mechanism of interaction involves the induction or inhibition of these proteins by co-administered drugs, which alters the systemic exposure (AUC and Cmax) of ozanimod and its long-lived active metabolites, CC-112273 and CC-1084037.