DIFFERENTIAL INTERACTION OF 3-HYDROXY-3-METHYLGLUTARYL-COA REDUCTASE INHIBITORS WITH ABCB1, ABCC2, AND OATP1B1

• Published in: Drug metabolism and disposition Vol. 33; no. 4; pp. 537 - 546
• Main Authors: CUIPING CHEN, MIRELES, Rouchelle J, CAMPBELL, Scott D, JIAN LIN, MILLS, Jessica B, XU, Jinghai J, SMOLAREK, Teresa A
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.04.2005
• Subjects: Adenosine Triphosphate - metabolism; Animals; Atorvastatin Calcium; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological and medical sciences; Cell Line; Dogs; Estradiol - analogs & derivatives; Estradiol - metabolism; Fluoresceins - metabolism; Heptanoic Acids - chemistry; Heptanoic Acids - pharmacokinetics; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors - chemistry; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacokinetics; Lovastatin - chemistry; Lovastatin - pharmacokinetics; Medical sciences; Membrane Transport Proteins - metabolism; Multidrug Resistance-Associated Proteins - metabolism; Organic Anion Transporters - metabolism; Permeability; Pharmacology. Drug treatments; Pyrroles - chemistry; Pyrroles - pharmacokinetics; Simvastatin - chemistry; Simvastatin - pharmacokinetics; Structure-Activity Relationship; Inhibitor; Oxidoreductases; Enzyme; Interaction; Reductase
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.104.002477

The present study examined the interaction of four 3-hydroxy-3-methylglutaryl coenzyme A 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 ratios [the ratio of the ratio of basolateral-to-apical apparent permeability and apical-to-basolateral permeability between MDR1 and MDCK] were 1.87, 2.32/4.46, 2.17/3.17, and 0.93/2.00 for pravastatin, atorvastatin (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 IC 50 values for efflux transporters (MDR1, MRP2, and Mrp2) were >100 μM for all statins in acid form except lovastatin acid (>33 μM), and the IC 50 values were up to 10-fold lower for the corresponding lactone forms. In contrast, the IC 50 values for the uptake transporter OATP1B1 were 3- to 7-fold lower for statins in the acid form compared with the corresponding lactone form. These data demonstrate that lactone and acid forms of statins exhibit differential substrate and inhibitor activities toward efflux and uptake transporters. The interconversion 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.