Differential Interaction of 3-Hydroxy-3-Methylglutaryl-Coa Reductase Inhibitors With Abcb1, Abcc2, and Oatp1b1

Abstract

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 basolateralto-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 M for all statins in acid form except lovastatin acid (>33 M), 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.

Clinical implications of pharmacogenomics of statin treatment

“…34 Hepatobiliary excretion of statins is mediated by ABCC2 and ABCB1 as well as ABCG2 and ABCB11, all of which belong to a family of transporters known to interact with lipophilic xenobiotics. [35][36][37][38][39][40] Variations in these transporters could alter duration of hepatic exposure, and therefore exposure to sites of action and to metabolizing enzymes. Variation in ABCC2, likely the largest contributor to biliary excretion of statins, is known to exhibit variation; however, this has been poorly studied in the context of statin transport.…”

Screening study for genetic polymorphisms affecting pharmacokinetics of simvastatin

“…[35] The ABCC2 gene is also involved in the inhibition of biliary excretion HMGR. [34,36,37] By whole genome linear regression analysis, we found several highly possible candidate SNPs which affecting PK parameters of simvastatin. Interestingly, except for few SNPs of phase I and phase II enzymes, such as CYP3A5 (C max ) (Supplemnetary Table 1) and CYP2F1 (T max ), most of the significant SNPs were found in transporters.…”

Pediatric Statin Administration: Navigating a Frontier with Limited Data

“…108,109 Notably, the simvastatin and lovastatin lactones appear to inhibit OATP1B1-mediated transport. 110,111 The clinical relevance of OATP-mediated statin disposition has been demonstrated in a number of drug-drug interaction studies. A 7-fold increase in the AUCs of atorvastatin acid and 2-hydroxy atorvastatin acid and a 3-fold increase in AUC of 4-hydroxy atorvastatin acid were observed when this statin was coadministered with rifampin (a known inhibitor of OATP1B1 and OATP1B3).…”