Received for publication September 22, 2004.
Revised December 20, 2004.
Accepted for publication December 22, 2004.

DIFFERENTIAL INTERACTION OF HMG-CoA REDUCTASE INHIBITORS WITH ABCB1, ABCC2, AND OATP1B1

Abstract

ABSTRACT The present study examined the interaction of four 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (atorvastatin, lovastatin, and simvastatin in acid and lactone forms and pravastatin in acid form only) with multidrug resistance gene 1 (MDR1, ABCB1) P-glycoprotein, multidrug resistance associated protein 2 (MRP2, ABCC2), and organic anion transporting polypeptide 1B1 (OATP1B1, SLCO21A6). P-glycoprotein substrate assays were performed using Madin-Darby Canine Kidney (MDCK) cells expressing MDR1 and the efflux ratio [the ratio of the ratio of basolateral-to-apical (B-A) apparent permeability and A-B between MDR1 and MDCK) was 1.87, 2.32/4.46, 2.17/3.17, 0.93/2.00 for pravastatin, atorvastain (lactone/acid), lovastatin (lactone/acid), and simvastatin (lactone/acid), respectively, indicating that these compounds are weak or moderate substrates of P-glycoprotein. In the inhibition assays (MDR1, MRP2, Mrp2, and OATP1B1), the IC₅₀ values (µM) for efflux transporters (MDR1, MRP2 and Mrp2) were >100 for all statins in acid form except lovastatin acid (>33) and the IC₅₀ values were up to 10-fold lower for the corresponding lactone forms. In contrast, the IC₅₀ values (µM) for the uptake transporter OATP1B1 were 3- to 7-fold lower for statins in the acid form compared to the corresponding lactone form. These data demonstrate that lactone and acid forms of statins exhibit differential substrate and inhibitor activities towards efflux and uptake transporters. The intercoversion between the lactone and acid forms of most statins exists in the body and will potentially influence drug transporter interactions and may ultimately contribute to the differences in pharmacokinetic profiles observed between statins.

Key words: drug transport, inhibition, MRP, organic anion transport, p-glycoprotein, structure-activity relationships

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