title: Evidence of drug-drug interactions through uptake and efflux transport systems in rat hepatocytes: implications for cellular concentrations of competing drugs.
abstract: For drugs with hepatobiliary transport across hepatocytes, the interplay between uptake and efflux transporters determines hepatic concentrations of drugs, but the evolution over time of these concentrations is difficult to measure in humans other than with magnetic resonance imaging contrast agents in the liver. Gadobenate dimeglumine (BOPTA) is a contrast agent used in liver magnetic resonance imaging that enters into human hepatocytes through organic anion transporting polypeptides (OATP) and exits unchanged into bile through the multiple resistance-associated protein 2 (MRP2). Rifampicin (RIF) is transported by the same membrane proteins and may compete with BOPTA for hepatic uptake. Simultaneous drug-drug interactions through uptake and efflux transport systems in hepatocytes according to the cellular concentrations of competing drugs were never investigated. In perfused rat liver preparations, we demonstrate how the drug-drug interactions through transporters determine cellular concentrations of the competing drugs BOPTA and RIF, and we show that the cellular concentrations by modulating transport through membranes regulate the rat Oatp-Mrp2 interplay. Moreover, drug interactions through transporters change greatly over time.
authors.affiliation: Service de Pharmacologie et Toxicologie Clinique, Laboratoire de Physiopathologie Hépatique et Imagerie Moléculaire, Hôpitaux Universitaires de Genève, Rue Gabrielle-Perret-Gentil, 4, 1205 Geneva, Switzerland.
authors.forename: Youssef
authors.initials: Y
authors.lastname: Daali
authors.forename: Philippe
authors.initials: P
authors.lastname: Millet
authors.forename: Pierre
authors.initials: P
authors.lastname: Dayer
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Pastor
mesh_terms: D000818:Animals; D001692:Biological Transport; D004347:Drug Interactions; D022781:Hepatocytes / Q000378:metabolism*; D008297:Male; D008536:Meglumine / Q000031:analogs & derivatives* / Q000378:metabolism; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000502:physiology*; D027361:Organic Anion Transporters / Q000502:physiology*; D009942:Organometallic Compounds / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012293:Rifampin / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D008536:Meglumine; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D009942:Organometallic Compounds; D012293:Rifampin; C000715087:ABCC2 protein, human; C064572:gadobenic acid