Cytochrome P450 2C19, Cytochrome P450 2C9, and Cytochrome P450 3A4 (CYP2C19, CYP2C9, CYP3A4)

Cytochrome P450 (CYP) enzymes, specifically the isoforms 2C19, 2C9, and 3A4, are critical heme-containing proteins located in the endoplasmic reticulum of hepatocytes that mediate the phase I metabolism of numerous drugs (Source: UniProt). These enzymes are responsible for the oxidative biotransformation of abrocitinib, a selective Janus kinase 1 (JAK1) inhibitor used to treat atopic dermatitis (Source: FDA Cibinqo Label). The specific interaction described involves the inhibition of these metabolic pathways by fluconazole, a triazole antifungal agent. Fluconazole acts as a strong inhibitor of CYP2C19 and a moderate inhibitor of CYP2C9 and CYP3A4, which significantly reduces the clearance of abrocitinib and its active metabolites (Source: PubChem). This inhibition results in a marked increase in the area under the curve (AUC) and peak plasma concentration (Cmax) of the drug, potentially leading to dose-dependent adverse effects such as thrombocytopenia and increased susceptibility to infections (Source: PubMed/PMID: 34333056). Beyond drug metabolism, these enzymes play roles in the synthesis of cholesterol, steroids, and other lipids, making them central to both pharmacology and endogenous homeostasis (Source: NIH/StatPearls). Consequently, clinical guidelines recommend reducing the dose of abrocitinib when co-administered with strong CYP2C19 inhibitors like fluconazole to maintain a safe therapeutic profile (Source: FDA Cibinqo Label).

Other names

CYP2C19CYP2C9CYP3A4Cytochrome P450 enzymesMicrosomal monooxygenaseHeme-thiolate proteins

Fluconazole inhibits the enzymatic activity of CYP2C19, CYP2C9, and CYP3A4, thereby reducing the metabolic clearance of abrocitinib and increasing its systemic exposure.