Regulation of drug and bile salt transporters in liver and intestine.
Major determinants of the bioavailability of drugs are the degree of intestinal absorption and the hepatic first-pass effect. Drugs need to overcome several membrane barriers before reaching the systemic circulation, each of which expresses an array of specialized transport proteins for drug uptake or efflux. The P-glycoprotein MDR1 (multidrug resistance gene product, ABCB1) is expressed at the apical surface of enterocytes, where it mediates the efflux of xenobiotics into the intestinal lumen before these can access the portal circulation. Increased expression of MDR1 reduces the bioavailability of MDR1 substrates such as digoxin, cyclosporin, and taxol. Numerous xenobiotics can induce the MDR1 gene through activation of the nuclear pregnane X receptor (PXR). This explains the risk for drug interactions that is inherent to pharmacotherapy with PXR ligands such as rifampin, phenobarbital, statins, and St. John's wort. Other PXR-regulated genes include cytochrome P450 3A4, the digoxin and bile salt transporter Oatp2 (organic anion transporting polypeptide 2, Slc01a4) of the basolateral hepatocyte membrane, and the xenobiotic efflux pump Mrp2 (multidrug resistance associated protein 2, Abcc2) of the canalicular hepatocyte membrane. A second orphan nuclear receptor that is activated by xenobiotics is the constitutive androstane receptor (CAR), which induces Mrp2 and Mrp3 (Abcc3). The PXR and CAR are thus important "xenosensors" that mediate drug-induced activation of the detoxifying transport and enzyme systems in liver and intestine.
Kullak-Ublick
Gerd A
GA
Laboratory of Molecular Gastroenterology and Hepatology, Division of Clinical Pharmacology and Toxicology, Department of Internal Medicine, University Hospital, Zurich, Switzerland. gerd.kullak@usz.ch
Becker
May-Britt
MB
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D027321:Anion Transport Proteins / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D000089762:Multidrug Resistance-Associated Protein 2; D004364:Pharmaceutical Preparations / Q000378:metabolism
C000715087:ABCC2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D027321:Anion Transport Proteins; D001647:Bile Acids and Salts; D000089762:Multidrug Resistance-Associated Protein 2; D004364:Pharmaceutical Preparations