RT Journal Article
SR Electronic
T1 Evidence of Drug-Drug Interactions through Uptake and Efflux Transport Systems in Rat Hepatocytes: Implications for Cellular Concentrations of Competing Drugs
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.113.051870
DO 10.1124/dmd.113.051870
A1 Youssef Daali
A1 Philippe Millet
A1 Pierre Dayer
A1 Catherine M Pastor
YR 2013
UL http://dmd.aspetjournals.org/content/early/2013/05/24/dmd.113.051870.abstract
AB 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, apart from liver imaging with magnetic resonance (MR) contrast agents. Gadobenate dimeglumine (BOPTA, MultiHance®, Bracco, Milan) is a contrast agent used in liver MR imaging that enters into human hepatocytes through Organic Anion Transporting Polypeptides (OATP) and exit unchanged into bile through the Multiple Resistance-associated Protein 2 (MRP2). Rifampicin 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 greatly change over time.