ATP-dependent transport of statins by human and rat MRP2/Mrp2

doi:10.1016/j.taap.2013.03.019

Toxicology and Applied Pharmacology

Volume 269, Issue 2, 1 June 2013, Pages 187-194

https://doi.org/10.1016/j.taap.2013.03.019 Get rights and content

Highlights

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We characterised MRP2 (human)/Mrp2 (rat)-mediated transport of statins.
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We show statins were transported by human and rat MRP2/Mrp2.
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Statins competed with a known substrate for transport by MRP2/Mrp2.
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Competition involved more than one binding site on the MRP2/Mrp2 protein.

Abstract

Multidrug resistance associated protein-2, MRP2 (human), Mrp2 (rat) are an efflux transporter, responsible for the transport of numerous endogenous and xenobiotic compounds including taurocholate, methotrexate and carboxydichlorofluorescein (CDF). The present study aims to characterise transport of statins by human and rat MRP2/Mrp2 using membrane and vesicle preparations. All statins tested (simvastatin, pravastatin, pitavastatin, fluvastatin, atorvastatin, lovastatin and rosuvastatin) stimulated vanadate-sensitive ATPase activity in membranes expressing human or rat MRP2/Mrp2, suggesting that all statins are substrates of human and rat MRP2/Mrp2. The substrate affinity (Km) of all statins for MRP2/Mrp2 was comparable and no correlation between lipophilicity (logD_7.0) and Km was seen. All statins also inhibited uptake of the fluorescent Mrp2 substrate, CDF (1 μM) into vesicles expressing human or rat MRP2/Mrp2 with similar IC₅₀ values. Fitting of the inhibitory data to the hill slope equation, gave hill coefficients (h) of greater than one, suggesting that transport involved more than one binding site for inhibitors of MPR2 and Mrp2. We conclude that statins were transported by both human and rat MRP2/Mrp2 with similar affinity. Statins were also shown to compete with other substrates for transport by MRP2/Mrp2 and that this transport involved more than one binding site on the Mrp2/MRP2 protein.

Introduction

Determination of human and rat pharmacokinetics of novel drug candidates is important at several stages of the drug development process (Lowe et al., 2007, Weaver and Jochemsen, 2009). Extrapolation from in vitro data to the in vivo situation and from animals to humans involving scaling factors and physiologically-relevant models has been used (Rostami-Hodjegan, 2012). This approach has been successful in scaling from rat to humans for hepatic metabolism and urinary excretion but not biliary excretion. A comparison of transport activity in normal and multidrug resistance-associated protein 2 (Mrp2) deficient rats (TR⁻/EHBR), has given insight into Mrp2 substrate specificity (Kitamura et al., 1990, Fernandez-Checa et al., 1992). However, with the cloning and expression of human and rat MRP2/Mrp2 in vesicles and membranes, direct quantification of transport can be made, without interferences from other transporters (Bodó et al., 2003).

Statins (HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitors) are an effective treatment for hypercholesterolemia (Pedersen et al., 1996, Lewis et al., 1998, Plehn et al., 1999, LaRosa et al., 2005). As such, statins have become one of the most commonly prescribed drugs in the world. For this reason, it is important to determine drug–drug interactions (DDIs) between statins and other drugs as this could potentially affect millions of individuals worldwide. Statins have been designed to be hepatoselective, as the main site of cholesterol synthesis is in the liver and inhibition of cholesterol synthesis at other sites may lead to adverse drug reactions (Hamelin and Turgeon, 1998). Hydrophilic statins e.g. pravastatin are more hepatoselective than lipophilic statins (Chapman and McTaggart, 2002, Link et al., 2004). Lipophilic statins can passively diffuse into tissues, whereas hydrophilic statins rely on drug transporters to enter cells. The main uptake transporters for statins are OATP1B1 and OATP1B3, which are liver-specific. Therefore, the OATP-mediated uptake of statins is crucial for the action of statins. The majority of statins are given orally as the active β-hydroxy acid form, with the exception of simvastatin and lovastatin, which are administered as the inactive lactone (Corsini et al., 1999, Reinoso et al., 2001). Lactone and acid forms of atorvastatin, lovastatin, cerivastatin and simvastatin have been detected in the systemic circulation of humans and/or animals after oral administration, suggesting that inter-conversion between both forms occurs in vivo (Neuvonen and Jalava, 1996, Kantola et al., 1998a, Kantola et al., 1998b, Backman et al., 2002). The lactone and acid forms of atorvastatin, lovastatin and simvastatin are substrates and inhibitors of the metabolising enzyme, CYP3A4, with the lactone forms of the statins showing stronger inhibition of CYP3A4-mediated metabolism of mexazolam than the corresponding acid form (Ishigami et al., 2001). The inhibition of CYP3A4-mediated metabolism of drugs by statins has been identified as one of the major causes of drug–drug interactions involving statins (Shitara et al., 2006). Drug efflux transporters, including MRP2 (ABCC2), P-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2) and the hepatic uptake transporters, OATP1B1 and OATP1B3, are involved in statin transport and are thought to contribute to the varying pharmacokinetic properties of statins (Shitara et al., 2003, Shitara et al., 2004, Chen et al., 2005, Hirano et al., 2005a, Hirano et al., 2005b, Huang et al., 2006).

The aim of this work was to use two membrane-based assays to determine if seven currently prescribed statins are substrates for human MRP2 or rat Mrp2 and to identify any species differences between rat and human in substrate specificity. This will allow us to comment on the suitability of rats to predict clearance in humans.

Section snippets

Materials

ATP (adenosine triphosphate magnesium salt), l-glutathione, 5(6)-carboxy-2′,7′-dichloro-fluorescein (CDF), DDT (dithiothreitol), EDTA (ethylenediaminetetraacetic acid), Mes (2-(N-morpholino) ethanesulfonic acid) hydrate, tris (tris(hydroxymethyl)aminomethane), MOPS (3-(N-morpholino)propanesulfonic acid), potassium chloride, sodium azide, sucrose and sodium orthovanadate were purchased from Sigma-Aldrich (U.K.). Pravastatin acid was purchased from Tocris Bioscience. Atorvastatin acid,

Statins stimulated ATPase activity in membranes expressing human or rat MRP2/Mrp2

MRP2/Mrp2 is an ATP-dependent transporter, which uses the energy created from the hydrolysis of ATP to transport substrates across a membrane. The hydrolysis of ATP yields inorganic phosphate, which is proportional to transporter activity. This assay can be used to distinguish between substrates and inhibitors, as transported substrates will significantly stimulate ATPase activity, whereas inhibitors will block the ATPase cycle.

All statins tested stimulated vanadate-sensitive ATPase activity in

Discussion

Membrane and vesicle preparations expressing transporters are a viable alternative to cell based assays, as determination of transport kinetics can be achieved without interference from endogenous transporters. Here we have used these techniques, to characterise Mrp2/MRP2-transport of statins. All statins stimulated ATPase activity in membranes expressing human and rat MRP2/Mrp2. As ATP hydrolysis is tightly linked with substrate transport, all statins were thus identified as substrates of

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Statins have beneficial effects on intrahepatic circulation and decrease portal hypertension and rifaximin modulates the gut microbiome and might prevent bacterial translocation in patients with cirrhosis. Therefore, this drug combination might be of therapeutic benefit in patients with decompensated cirrhosis. However, there is concern regarding the safety of statins in patients with decompensated cirrhosis. We assessed the safety of two different doses of simvastatin, in combination with rifaximin, in patients with decompensated cirrhosis.
We did a double-blind, randomised, placebo-controlled, phase 2 trial in patients with decompensated cirrhosis and moderate-to-severe liver failure from nine university hospitals in six European countries (Italy, France, Holland, Germany, the UK, and Spain). Patients older than 18 years with Child-Pugh class B or C disease were eligible. We randomly assigned patients (1:1:1) to receive either simvastatin 40 mg/day plus rifaximin 1200 mg/day, simvastatin 20 mg/day plus rifaximin 1200 mg/day, or placebo of both medications for 12 weeks. Randomisation was stratified according to Child-Pugh class (B vs C) and restricted using blocks of multiples of three. The primary endpoint was development of liver or muscle toxicity, as defined by changes in liver aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), alkaline phosphastase, and creatine kinase. The study is registered with the European Union Clinical Trials Register, 2016-004499-23, and with ClinicalTrials.gov, NCT03150459.
The study recruitment period was between July 28, 2017, and Jan 2, 2018. Follow-up finished on March 12, 2018. 50 patients were randomly assigned to simvastatin 40 mg/day plus rifaximin 1200 mg/day (n=18), simvastatin 20 mg/day plus rifaximin 1200 mg/day (n=16), or placebo of both medications (n=16). Six patients (two from each group) were excluded. Therefore, the full analysis set included 44 patients (16 in the simvastatin 40 mg/day plus rifaximin 1200 mg/day group, 14 in the simvastatin 20 mg/day plus rifaximin mg/day group, and 14 in the placebo group). After a safety analyses when the first ten patients completed treatment, treatment was stopped prematurely in the simvastatin 40 mg/day plus rifaximin group due to recommendations by the data safety monitoring board. Patients in the simvastatin 40 mg/day plus rifaximin group showed a significant increase in AST and ALT compared with the placebo group (mean differences between the groups at the end of treatment for AST 130 IU/L [95% CI 54 to 205; p=0·0009] and for ALT 61 IU/L [22 to 100; p=0·0025]. We observed no significant differences at 12 weeks in AST and ALT between the simvastatin 20 mg/day plus rifaximin and placebo group (for AST −14 IU/L [–91 to 64; p=0·728] and for ALT −8 IU/L [–49 to 33; p=0·698]). We observed no significant differences in alkaline phosphatase between the the simvastatin 40 mg/day plus rifaximin or the simvastatin 20 mg/day plus rifaximin groups compared with placebo. Patients in the simvastatin 40 mg/day plus rifaximin group showed an increase in creatine kinase at the end of treatment compared with patients in the placebo group (1009 IU/L [208 to 1809]; p=0·014). We observed no significant changes in creatine kinase in the simvastatin 20 mg/day plus rifaximin group (4·2 IU/L [–804 to 813]; p=0·992). Three (19%) patients in the simvastatin 40 mg/day group developed liver and muscle toxicity consistent with rhabdomyolysis. The number of patients who stopped treatment because of adverse events was significantly higher in the simvastatin 40 mg/day plus rifaximin group (nine [56%] of 16 patients) compared with the other two groups (two [14%] of 14 for both groups; p=0·017). There were no serious unexpected adverse reactions reported during the study.
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The present study investigated whether the clinical pharmacokinetics of atorvastatin can be predicted from the results of microdosing study in Japanese patients with hypercholesterolemia whose SLCO1B1 and ABCG2 polymorphisms were analyzed. Forty seven statin-naive patients clinically indicated to LDL cholesterol-lowering therapy with atorvastatin were enrolled in a two-period crossover study. Microdose (100 μg) of atorvastatin was orally administered followed by therapeutic dose (10 mg) administration. Transport studies were performed with BCRP-expressing membrane vesicles. The dose-normalized plasma AUC following the therapeutic dose of atorvastatin was positively correlated with that following its microdose, but the AUC increased more than dose proportionally from microdose to therapeutic dose. The patients carrying SLCO1B1 c.521TC showed a significantly higher AUC compared with those carrying c.521TT following the microdose (175%) and therapeutic dose (139%). On the other hand, SLCO1B1 c.388G or ABCG2 c.421A variant alleles did not significantly affect the pharmacokinetics of atorvastatin. Atorvastatin showed ATP-dependent transport in BCRP-expressing membrane vesicles and it inhibited rosuvastatin transport with K_i of 6.3 ± 2.9 μM (mean ± SD). Microdosing study appears to be feasible to roughly estimate the pharmacokinetic and pharmacogenetic profiles of atorvastatin following the oral therapeutic dose in hypercholesterolemic patients.
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Citation Excerpt :
Our data indicated that the gene expression level of MRP2 in SCHepG2 and SCHepG2-hNTCP-C4 cells was similar to that in HPHs at 48 h, and MRP2 activity was also observed. Importantly, some statins are excreted via MRP2 and exhibit hepatotoxicity (Ellis et al., 2013). In this study, statins caused cell toxicity in the presence of BAs in SCHepG2-hNTCP-C4 cells but not in SCHepG2 cells.
Toxicological approaches in screening drugs that cause drug-induced liver injury (DILI) are urgently needed to reduce the risk of developing DILI and avoid immense costs resulting from late-stage drug withdrawal from clinical trials. Cholestatic DILI is characterized by bile acid (BA) accumulation in hepatocytes, typically caused by drug-induced inhibition of important bile transporters, such as bile salt export pump (BSEP) and multidrug resistance-associated protein 2/3/4 (MRP2/3/4). Therefore, NTCP expression is essential for construction of an in vitro hepatocellular toxicity evaluation system. Here, we investigated whether sandwich-cultured HepG2-hNTCP-C4 (SCHepG2-hNTCP-C4) cells were applicable for evaluation of cholestatic DILI. In SCHepG2-hNTCP-C4 cells, NTCP and MRP2/4 expression levels were comparable to those in human primary hepatocytes; however, BSEP expression was low. In addition, the substrates tauro-nor-THCA-24 DBD and CDF confirmed the functionality of NTCP and MRP2, respectively. When 22 known hepatotoxins were exposed to BAs to evaluate cholestatic DILI, cytotoxicity in SCHepG2-hNTCP-C4 cells was more frequent than that in SCHepG2 cells. Thus, SCHepG2-hNTCP-C4 cells may be useful preclinical screening tools to predict the risk of cholestatic DILI induced by drug candidates. However, further studies are needed to determine why the cholestatic cytotoxicity of some compounds would be still insufficient in SCHepG2-hNTCP-C4 cells.

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ATP-dependent transport of statins by human and rat MRP2/Mrp2

Highlights

Abstract

Introduction

Section snippets

Materials

Statins stimulated ATPase activity in membranes expressing human or rat MRP2/Mrp2

Discussion

Toxicol. Lett.

Atheroscler. Suppl.

Pharmacol. Ther.

J. Biol. Chem.

Trends Pharmacol. Sci.

J. Biol. Chem.

J. Am. Coll. Cardiol.

Bioorg Med Chem Lett

Atheroscler. Suppl.

Eur. J. Pharm. Sci.

J Biol Chem

Gemfibrozil greatly increases plasma concentrations of cerivastatin

Clin. Pharmacol. Ther.

HMG-CoA reductase inhibitors and P-glycoprotein modulation

Br. J. Pharmacol.

Rhabdomyolysis with HMG-CoA reductase inhibitors and gemfibrozil combination therapy

Pharmacoepidemiol Drug Saf

Differential interaction of 3-hydroxy-3-methylglutaryl-coa reductase inhibitors with ABCB1, ABCC2, and OATP1B1

Drug Metab Dispos

Multiple inhibition mechanisms and prediction of drug–drug interactions: status of metabolism and transporter models as exemplified by gemfibrozil–drug interactions

Pharm. Res.

Bile salt export pump (BSEP/ABCB11) can transport a nonbile acid substrate, pravastatin

J. Pharmacol. Exp. Ther.

Involvement of BCRP (ABCG2) in the biliary excretion of pitavastatin

Mol. Pharmacol.

Drug–drug interaction between pitavastatin and various drugs via OATP1B1

Drug Metab Dispos

ATP-dependent transport of rosuvastatin in membrane vesicles expressing breast cancer resistance protein

Drug Metab Dispos

A comparison of the effects of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors on the CYP3A4-dependent oxidation of mexazolam in vitro

Drug Metab Dispos

Pitavastatin: efficacy and safety profiles of a novel synthetic HMG-CoA reductase inhibitor

Cardiovasc Drugs Rev

Effect of itraconazole on the pharmacokinetics of atorvastatin

Clin. Pharmacol. Ther.

Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations

Clin. Pharmacol. Ther.