ATP-dependent transport of statins by human and rat MRP2/Mrp2.
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Ellis LC, Hawksworth GM, Weaver RJ
ATP-dependent transport of statins by human and rat MRP2/Mrp2.
Toxicol Appl Pharmacol. 2013 Jun 1;269(2):187-94. doi: 10.1016/j.taap.2013.03.019. Epub 2013 Apr 2.
- PubMed ID
- 23562342 [ View in PubMed]
- Abstract
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 (1muM) 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.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Fluvastatin Canalicular multispecific organic anion transporter 1 Protein Humans NoSubstrateDetails Lovastatin Canalicular multispecific organic anion transporter 1 Protein Humans UnknownSubstrateDetails Rosuvastatin Canalicular multispecific organic anion transporter 1 Protein Humans NoSubstrateDetails