ATP-dependent transport of statins by human and rat MRP2/Mrp2

• Published in: Toxicology and applied pharmacology Vol. 269; no. 2; pp. 187 - 194
• Main Authors: Ellis, Lucy C.J., Hawksworth, Gabrielle M., Weaver, Richard J.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.06.2013; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; Adenosine Triphosphate - metabolism; Animals; ATP; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; ATPase assay; BILE; Biological and medical sciences; Biological Transport - physiology; Cell Membrane; CONCENTRATION RATIO; Drug interactions; FLUORESCENCE; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - metabolism; Insecta - cytology; MAMMARY GLANDS; Medical sciences; METHOTREXATE; MRP2; Multidrug Resistance-Associated Proteins - genetics; Multidrug Resistance-Associated Proteins - metabolism; NEOPLASMS; Pharmacokinetics; POLYPEPTIDES; POTASSIUM IODIDES; RATS; Statins; Toxicology; TRANSPORT; Vesicle assay; BCRP; MOPS; Km; MRP2; BSEP; SDS; CDF; ATPase assay; Vmax; Drug interactions; EDTA; OATP1B1; TRIS; HMGR; DDIs; DDT; CYP450; IC50; Vesicle assay; Mes; Pharmacokinetics; Ki; Statins; Human; Vesicle; Rat; Enzyme; Rodentia; Adenosinetriphosphatase; Statin derivative; Vertebrata; Mammalia; Animal; Hydrolases; Drug interaction; Transport; ABC transporter; ATP; Multidrug resistance protein 2; Antilipemic agent
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2013.03.019

Multidrug resistance associated protein-2, MRP2 (human), Mrp2 (rat) are an efflux transporter, responsible for the transport of numerous endogenous and xenobiotic compounds including taurocholate, methotrexate and carboxydichlorofluorescein (CDF). The present study aims to characterise transport of statins by human and rat MRP2/Mrp2 using membrane and vesicle preparations. All statins tested (simvastatin, pravastatin, pitavastatin, fluvastatin, atorvastatin, lovastatin and rosuvastatin) stimulated vanadate-sensitive ATPase activity in membranes expressing human or rat MRP2/Mrp2, suggesting that all statins are substrates of human and rat MRP2/Mrp2. The substrate affinity (Km) of all statins for MRP2/Mrp2 was comparable and no correlation between lipophilicity (logD7.0) and Km was seen. All statins also inhibited uptake of the fluorescent Mrp2 substrate, CDF (1μM) into vesicles expressing human or rat MRP2/Mrp2 with similar IC50 values. Fitting of the inhibitory data to the hill slope equation, gave hill coefficients (h) of greater than one, suggesting that transport involved more than one binding site for inhibitors of MPR2 and Mrp2. We conclude that statins were transported by both human and rat MRP2/Mrp2 with similar affinity. Statins were also shown to compete with other substrates for transport by MRP2/Mrp2 and that this transport involved more than one binding site on the Mrp2/MRP2 protein. •We characterised MRP2 (human)/Mrp2 (rat)-mediated transport of statins.•We show statins were transported by human and rat MRP2/Mrp2.•Statins competed with a known substrate for transport by MRP2/Mrp2.•Competition involved more than one binding site on the MRP2/Mrp2 protein.