Cytochrome P450 3A4 and Cytochrome P450 2B6 (CYP3A4/CYP2B6)

Cytochrome P450 3A4 (CYP3A4) and Cytochrome P450 2B6 (CYP2B6) are critical hepatic enzymes responsible for the phase I metabolism of a wide array of xenobiotics, including the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine [1, 4, 9]. CYP3A4 is the most abundant cytochrome P450 in the human liver and is involved in the metabolism of approximately 50% of all clinical drugs, while CYP2B6, though less abundant, plays a significant role in the clearance of specific drugs like nevirapine and efavirenz [3, 5, 13]. The interaction described involves the inhibition of these enzymes by fluconazole, a triazole antifungal agent, which significantly impairs the metabolic clearance of nevirapine [1, 7, 14]. This pharmacokinetic interaction results in elevated nevirapine plasma concentrations, which may increase the risk of serious adverse effects such as hepatotoxicity and severe skin reactions [1, 8, 15]. Understanding the interplay between these enzymes and their inhibitors is vital for managing complex drug regimens in patients with HIV and opportunistic fungal infections [11, 16]. Genetic polymorphisms in these enzymes, particularly CYP2B6, further contribute to significant inter-individual variability in drug exposure and clinical outcomes [2, 12].

Other names

CYP3A4CYP2B6Cytochrome P450 3A4Cytochrome P450 2B6Nevirapine metabolizing enzymes

Fluconazole acts as a competitive and non-competitive inhibitor of the Cytochrome P450 enzymes CYP3A4 and CYP2B6, which are the primary enzymes responsible for the oxidative metabolism of Nevirapine. By inhibiting these enzymes, fluconazole reduces the metabolic clearance of Nevirapine, leading to increased systemic exposure (AUC) and peak plasma concentrations (Cmax).