Functional interactions between P-glycoprotein and CYP3A in drug metabolism

Uwe Christians, Volker Schmitz, Manuel Haschke
2005 Expert Opinion on Drug Metabolism & Toxicology  
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)
more » ... P3A; 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. Keywords: cytochrome P450, drug-drug interactions, drug metabolism, drug transport, oral bioavailability, P-glycoprotein, pharmacokinetic variability Expert Opin. Drug Metab. Toxicol. (2005) 1(4):xxx-xxx 1. Introduction 2. Functional interactions between CYP3A and P-glycoprotein in the small intestine 3. Different functional interactions between CYP3A and P-glycoprotein in the liver and small intestine and impact on drug-drug interactions 4. Coregulation of CYP3A and P-glycoprotein 5. Sources of variability 6. Impact on drug development 7. Expert opinion A u t h o r P r o o f Functional interactions between P-glycoprotein and CYP3A in drug metabolism 2 A u t h o r P r o o f Christians, Schmitz & Haschke Expert Opin. Drug Metab. Toxicol. (2005) 1(4) 21. CUMMINS CL, JACOBSEN W,
doi:10.1517/17425255.1.4.641 pmid:16863430 fatcat:uf6pfymnzjezpkqhwytemwttaa