CYP3A4

CYP3A4 is a member of the cytochrome P450 enzyme family and plays a central role in the metabolism of many drugs and endogenous compounds. It is one of the most important drug‑metabolizing enzymes, responsible for the oxidation of a large proportion of clinically used medications. CYP3A4 is primarily expressed in the liver and the intestinal wall, where it resides in the endoplasmic reticulum of hepatocytes and enterocytes and participates in monooxygenation reactions that require NADPH.

The enzyme has a broad substrate range and metabolizes steroids, bile acids, fatty acids, and a wide variety of xenobiotics. Its high capacity and broad specificity contribute to substantial interindividual variability in drug clearance. Expression levels are influenced by genetic factors, environmental exposures, autoimmune or hepatic conditions, and concomitant drug therapy. The CYP3A4 gene is part of the CYP3A cluster; among common genetic variants, CYP3A4*22 is associated with reduced hepatic expression and slower clearance for some substrates. Regulation is mediated by nuclear receptors such as PXR and CAR; transcription can be induced by certain drugs and dietary compounds, increasing metabolism.

Clinical relevance arises from drug interactions and variability in drug response. Inducers like rifampin, phenobarbital, and St. John’s wort can lower plasma levels of coadministered drugs by enhancing metabolism, while inhibitors such as ketoconazole, ritonavir, and intestinal grapefruit juice can raise drug exposure by reducing CYP3A4 activity. These interactions are important considerations for dose adjustment, especially in polypharmacy, pediatrics, and liver disease.