Cytochrome P450 3A4, Cytochrome P450 3A5, and P-glycoprotein (CYP3A4/5 and P-gp)

The Cytochrome P450 3A4/5 and P-glycoprotein (P-gp) complex represents the most significant biochemical barrier to drug absorption and disposition in humans [1, 4]. CYP3A4 and CYP3A5 are heme-containing enzymes located primarily in the liver and small intestine that catalyze the oxidative metabolism of approximately 50% of all marketed drugs [2, 7]. P-glycoprotein, encoded by the ABCB1 gene, is an ATP-dependent efflux transporter co-localized with CYP3A in the intestinal epithelium and the blood-brain barrier [1, 10]. These proteins work synergistically; P-gp pumps substrates back into the intestinal lumen, providing CYP3A enzymes with repeated opportunities to metabolize the drug, thereby significantly reducing oral bioavailability [4, 12]. This 'CYP3A/P-gp axis' is a critical focal point for drug-drug interactions, as many compounds act as dual substrates, inhibitors, or inducers of both systems [2, 3]. Understanding their combined activity is essential for predicting pharmacokinetics, avoiding toxicity, and overcoming multidrug resistance in therapeutic areas such as oncology and infectious disease [5, 15]. Genetic polymorphisms in these proteins, such as the CYP3A5*3 allele, further contribute to significant inter-individual variability in drug response [7, 14].

Other names

ABCB1 [14]MDR1 [1, 12]Multidrug resistance protein 1 [1, 10]CYP3A4 [7]CYP3A5 [7]CYP3A/P-gp axis [4]Cytochrome P450 3A4 [7]Cytochrome P450 3A5 [7]

CYP3A4/5: Phase I oxidative metabolism (hydroxylation, N-dealkylation) [7, 11]. P-gp: ATP-dependent efflux from cells [1, 10]. Synergistic barrier to drug absorption [4, 12].