title: Functional interactions between P-glycoprotein and CYP3A in drug metabolism.
abstract: The interaction between drug-metabolising enzymes and active transporters is an emerging concept in pharmacokinetics. In the gut mucosa, P-glycoprotein and cytochrome P450 (CYP)3A functionally interact in three ways: i) drugs are repeatedly taken up and pumped out of the enterocytes by P-glycoprotein, thus increasing the probability of drugs being metabolised; ii) P-glycoprotein keeps intracellular drug concentrations within the linear range of the metabolising capacity of CYP3A; and iii) P-glycoprotein transports drug metabolites formed in the mucosa back into the gut lumen. In comparison with the gut mucosa, in hepatocytes the spatial sequence of CYP3A and P-glycoprotein is reversed, resulting in different effects when the activity of one or both are changed. CYP3A and P-glycoprotein are both regulated by nuclear receptors such as the pregnane X receptor (PXR). There is significant genetic variability of CYP3A, P-glycoprotein and PXR and their expression and activity is dependent on coadministered drugs, herbs, food, age, hormonal status and disease. Future pharmacogenomic and pharmacokinetic studies will have to take all three components into account to allow for valid conclusions.
authors.affiliation: University of Colorado Health Sciences Center, Clinical Research & Development, Department of Anesthesiology, Denver, Colorado 80262, USA. uwe.christians@uchsc.edu
authors.forename: Uwe
authors.initials: U
authors.lastname: Christians
authors.forename: Volker
authors.initials: V
authors.lastname: Schmitz
authors.forename: Manuel
authors.initials: M
authors.lastname: Haschke
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000818:Animals; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A / Q000502:physiology*; D015195:Drug Design; D004347:Drug Interactions; D018565:Food-Drug Interactions; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010597:Pharmacogenetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004364:Pharmaceutical Preparations; D051544:Cytochrome P-450 CYP3A