Transport of statins by human ABC efflux transporters in vitro

Transporters are cell membrane proteins, which mediate the cellular influx or efflux of compounds. Transporters expressed in tissues important for pharmacokinetics, can play a crucial role in drug absorption, distribution and excretion. Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and are used to treat hypercholesterolemia and to prevent cardiovascular diseases. Statins are usually well-tolerated and most adverse effects are mild. Statin-induced muscle toxicity is generally dose- and concentration-dependent. The inhibition of statin transport can alter statin plasma concentrations and thus the risk of adverse effects. The aim of the study was to characterize the transport of atorvastatin, fluvastatin, pitavastatin, pravastatin and rosuvastatin via ABC efflux transporters, including breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) 2-4 and 8 in vitro. Vesicular transport assays were used to investigate statin transport through specific efflux transporters. The transport studies were divided into three parts: screening of statin transport, time-linearity of transport and concentration-dependent transport. The results demonstrated that atorvastatin and pitavastatin are substrates of BCRP, P-gp and MRP3, fluvastatin is a substrate of BCRP, P-gp, MRP2, MRP3 and MRP4, pravastatin is a substrate of MRP3 and rosuvastatin is a substrate of BCRP, P-gp and MRP4 in vitro. Simvastatin acid was not transported by any of the studied transporters. This thesis improves general understanding of pharmacokinetic properties of atorvastatin, fluvastatin, pitavastatin, pravastatin and rosuvastatin. These data are useful in predicting the effects of transporter-mediated drug-drug interactions and genetic variability in transporter function on the pharmacokinetics, efficacy and safety of statin therapy

Comparative Hepatic and Intestinal Efflux Transport of Statins

Previous studies have shown that lipid-lowering statins are transported by various ATP-binding cassette (ABC) transporters. However, because of varying methods, it is difficult to compare the transport profiles of statins. Therefore, we investigated the transport of 10 statins or statin metabolites by six ABC transporters using human embryonic kidney cell-derived membrane vesicles. The transporter protein expression levels in the vesicles were quantified with liquid chromatography-tandem mass spectrometry and used to scale the measured clearances to tissue levels. In our study, apically expressed breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) transported atorvastatin, fluvastatin, pitavastatin, and rosuvastatin. Multidrug resistance-associated protein 3 (MRP3) transported atorvastatin, fluvastatin, pitavastatin, and, to a smaller extent, pravastatin. MRP4 transported fluvastatin and rosuvastatin. The scaled clearances suggest that BCRP contributes to 87%-91% and 84% of the total active efflux of rosuvastatin in the small intestine and the liver, respectively. For atorvastatin, the corresponding values for P-gp-mediated efflux were 43%-79% and 66%, respectively. MRP3, on the other hand, may contribute to 23%-26% and 25%-37% of total active efflux of atorvastatin, fluvastatin, and pitavastatin in jejunal enterocytes and liver hepatocytes, respectively. These data indicate that BCRP may play an important role in limiting the intestinal absorption and facilitating the biliary excretion of rosuvastatin and that P-gp may restrict the intestinal absorption and mediate the biliary excretion of atorvastatin. Moreover, the basolateral MRP3 may enhance the intestinal absorption and sinusoidal hepatic efflux of several statins. Taken together, the data show that statins differ considerably in their efflux transport profiles. SIGNIFICANCE STATEMENT This study characterized and compared the transport of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin acid and four atorvastatin metabolites by six ABC transporters (BCRP, MRP2, MRP3, MRP4, MRP8, P-gp). Based on in vitro findings and protein abundance data, the study concludes that BCRP, MRP3, and P-gp have a major impact in the efflux of various statins. Together with in vitro metabolism, uptake transport, and clinical data, our findings are applicable for use in comparative systems pharmacology modeling of statins.Peer reviewe