Multiple Cytochrome P450 isoforms and P-glycoprotein (CYP/P-gp)

Multiple Cytochrome P450 (CYP450) isoforms and P-glycoprotein (P-gp) constitute the most significant biochemical and physical barriers to drug absorption and disposition in humans (StatPearls, 2023). CYP450 enzymes, such as CYP3A4, CYP2D6, and CYP2C9, are primarily responsible for the Phase I oxidative metabolism of xenobiotics in the liver and small intestine (PubMed: 23454733). P-glycoprotein, encoded by the ABCB1 gene, is an ATP-dependent efflux transporter that pumps drugs out of cells, particularly in the intestinal epithelium, hepatocytes, renal tubules, and the blood-brain barrier (UniProt: P08183). These two systems often exhibit overlapping substrate specificity and work in tandem to reduce the bioavailability of many orally administered drugs (PubMed: 15901328). While they are not typically the primary therapeutic targets for disease treatment, they are critical pharmacokinetic determinants that dictate the safety and efficacy profiles of almost all small-molecule drugs. Modulation of these proteins through induction or inhibition is a leading cause of clinically significant drug-drug interactions and can lead to multidrug resistance in cancer therapy (NIH: PMC3538395).

Other names

Cytochrome P450 and ABCB1CYP and MDR1Phase I metabolism and efflux transport systemCYP450 and P-glycoprotein complexXenobiotic metabolizing enzymes and transporters

Drugs act as substrates, inhibitors, or inducers of these proteins, modulating the systemic exposure, bioavailability, and intracellular concentration of various therapeutic agents (FDA Drug Development and Drug Interactions, 2020).