title: Differential interaction of 3-hydroxy-3-methylglutaryl-coa reductase inhibitors with ABCB1, ABCC2, and OATP1B1.
abstract: 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 IC50 values for efflux transporters (MDR1, MRP2, and Mrp2) were >100 microM for all statins in acid form except lovastatin acid (>33 microM), and the IC50 values were up to 10-fold lower for the corresponding lactone forms. In contrast, the IC50 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.
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, MS4044, Eastern Point Rd, Groton, CT 06340, USA. cuiping_chen@groton.pfizer.com
authors.forename: Cuiping
authors.initials: C
authors.lastname: Chen
authors.forename: Rouchelle J
authors.initials: RJ
authors.lastname: Mireles
authors.forename: Scott D
authors.initials: SD
authors.lastname: Campbell
authors.forename: Jian
authors.initials: J
authors.lastname: Lin
authors.forename: Jessica B
authors.initials: JB
authors.lastname: Mills
authors.forename: Jinghai J
authors.initials: JJ
authors.lastname: Xu
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Smolarek
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000069059:Atorvastatin; D002460:Cell Line; D004285:Dogs; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism; D005452:Fluoresceins / Q000378:metabolism; D006538:Heptanoic Acids / Q000737:chemistry / Q000493:pharmacokinetics; D006868:Hydrolysis; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics*; D008148:Lovastatin / Q000737:chemistry / Q000493:pharmacokinetics; D026901:Membrane Transport Proteins / Q000378:metabolism*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000378:metabolism*; D010539:Permeability; D011758:Pyrroles / Q000737:chemistry / Q000493:pharmacokinetics; D019821:Simvastatin / Q000737:chemistry / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000255:Adenosine Triphosphate; D000069059:Atorvastatin; D004958:Estradiol; D005452:Fluoresceins; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D011758:Pyrroles; D019821:Simvastatin; C025483:estradiol-17 beta-glucuronide; C007740:fluorexon