Biliary efflux transporters involved in the clearance of rosuvastatin in sandwich culture of primary rat hepatocytes

Jemnitz, Katalin; Veres, Zsuzsa; Tugyi, Regina; Vereczkey, L.

doi:10.1016/j.tiv.2009.10.009

Cited by 33 publications

(27 citation statements)

References 29 publications

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“…One is to preincubate and perform the uptake phase in standard (1Ca 21 ) HBSS, followed by a brief wash and efflux in Ca 21 -free HBSS [ Fig. 1A(ii)] (Jemnitz et al, 2010;Swift et al, 2010b). A limitation of this approach is that substrate accumulation in bile networks during the uptake phase may not be washed away completely before initiating the efflux phase in Ca 21 -free HBSS.…”

Section: Discussionmentioning

confidence: 99%

“…Active uptake into hepatocytes is facilitated by multiple organic anion transporting polypeptide (OATP) isoforms; sodium-taurocholate cotransporting polypeptide also has been reported to play a role (Ho et al, 2006;Abe et al, 2008;Kitamura et al, 2008). MRP2 and BCRP are the canalicular proteins primarily responsible for RSV biliary excretion (Huang et al, 2006;Kitamura et al, 2008;Keskitalo et al, 2009;Jemnitz et al, 2010;Hobbs et al, 2012). The role of basolateral transport proteins in RSV efflux from hepatocytes back into sinusoidal blood has not been examined.…”

Section: Introductionmentioning

confidence: 99%

“…A number of pharmacokinetic parameters can be calculated from uptake data (typically evaluated over a time period of 10 minutes), including the total substrate accumulation in cells 1 bile and cells, biliary excretion index, and in vitro clearance for uptake (CL Uptake ) and/or biliary excretion (CL Bile ), which can be used to predict in vivo clearance values based on scaling factors such as protein content and hepatocellularity (Swift et al, 2010a). Less frequently, the SCH model has been used to assess efflux by preloading cells with substrates (6 inhibitors), followed by an efflux phase, and quantifying substrate in cells 1 bile, cells, and/or appearance in buffer (Jemnitz et al, 2010;Swift et al, 2010b). However, the SCH system has not been characterized under these conditions.…”

Section: Introductionmentioning

confidence: 99%

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Hepatic Basolateral Efflux Contributes Significantly to Rosuvastatin Disposition I: Characterization of Basolateral Versus Biliary Clearance Using a Novel Protocol in Sandwich-Cultured Hepatocytes

Pfeifer

Yang

Brouwer

2013

J Pharmacol Exp Ther

103

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Transporters responsible for hepatic uptake and biliary clearance (CL Bile ) of rosuvastatin (RSV) have been well characterized. However, the contribution of basolateral efflux clearance (CL BL ) to hepatic and systemic exposure of RSV is unknown. Additionally, the appropriate design of in vitro hepatocyte efflux experiments to estimate CL Bile versus CL BL remains to be established. A novel uptake and efflux protocol was developed in sandwich-cultured hepatocytes (SCH) to achieve desired tight junction modulation while maintaining cell viability. Subsequently, studies were conducted to determine the role of CL BL in the hepatic disposition of RSV using SCH from wild-type (WT) and multidrug resistance-associated protein 2 (Mrp2)-deficient (TR 2 ) rats in the absence and presence of the P-glycoprotein and breast cancer resistance protein (Bcrp) inhibitor elacridar (GF120918). RSV CL Bile was nearly ablated by GF120918 in TR 2 SCH, confirming that Mrp2 and Bcrp are responsible for the majority of RSV CL Bile . Pharmacokinetic modeling revealed that CL BL and CL Bile represent alternative elimination routes with quantitatively similar contributions to the overall hepatocellular excretion of RSV in rat SCH under baseline conditions (WT SCH in the absence of GF120918) and also in human SCH. Membrane vesicle experiments revealed that RSV is a substrate of MRP4 (K m 5 21 6 7 mM, V max 5 1140 6 210 pmol/min per milligram of protein). Alterations in MRP4-mediated RSV CL BL due to drug-drug interactions, genetic polymorphisms, or disease states may lead to changes in hepatic and systemic exposure of RSV, with implications for the safety and efficacy of this commonly used medication.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hepatic Basolateral Efflux Contributes Significantly to Rosuvastatin Disposition I: Characterization of Basolateral Versus Biliary Clearance Using a Novel Protocol in Sandwich-Cultured Hepatocytes

Pfeifer

Yang

Brouwer

2013

J Pharmacol Exp Ther

103

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“…To improve such in vitro to in vivo extrapolation through physiologically based pharmacokinetic predictions (e.g., SimCYP), it is crucial to quantify the expression of transporters mediating the efflux of drugs and their metabolites. MRP2, encoded by the ABCC2 gene, is an important member of these efflux transporters, mediating the biliary efflux of a wide variety of drugs (e.g., fexofenadine, statins, spiramycin) and their phase II metabolites (glutathione and glucuronide conjugates) (Tian et al, 2007(Tian et al, , 2008Ieiri et al, 2009;Jemnitz et al, 2010). Although the expression of MRP2 in human livers has been previously quantified (Li et al, , 2009Ohtsuki et al, 2012), the small sample size did not provide an accurate estimate of the interindividual variability in the expression of this transporter.…”

Section: Introductionmentioning

confidence: 99%

Interindividual Variability in Hepatic Expression of the Multidrug Resistance-Associated Protein 2 (MRP2/ABCC2): Quantification by Liquid Chromatography/Tandem Mass Spectrometry

Deo¹,

Prasad²,

Balogh³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Multidrug-associated protein 2 (MRP2) is an efflux transporter that is expressed at the bile canalicular membrane. To allow in vitro to in vivo extrapolation of the contribution of MRP2 toward hepatic disposition of its substrates, data on the interindividual variability of hepatic MRP2 protein expression are required. Therefore, we quantified the expression of MRP2 in the University of Washington (UW) human liver bank (n ‫؍‬ 51) using a modified version of a previously validated liquid chromatography/ tandem mass spectrometry assay. An unlabeled (LTIIPQDPILFSGSLR) and stable isotope-labeled (LTIIPQDPILFSGSL[ Quality control samples created by spiking human serum albumin or pooled human liver (n ‫؍‬ 51) matrix with three different MRP2 synthetic peptide concentrations generated error and precision values of less than 15%. As determined by the surrogate peptide, the average MRP2 expression in the UW liver bank samples was 1.54 ؎ 0.64 fmol/g liver membrane protein and was found to be independent of age (7-63 years) or sex. A single nucleotide polymorphism in the promoter region (rs717620), previously thought to affect MRP2 expression, did not influence hepatic expression of MRP2. In contrast, the single nucleotide polymorphism 21214G>A (V417I; rs2273697) was associated with significantly higher hepatic MRP2 expression.

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“…There is convincing evidence showing that human ABCG2 is the major determinant of the pharmacokinetics and lipid-lowering effect of rosuvastatin ( 5 ). In addition, it has been suggested that another effl ux transporter, ABCC2, is involved in the biliary excretion of rosuvastatin in humans ( 18 ), whereas animal studies in rats identifi ed a possible role of bile acid export pump (Bsep) in the biliary clearance of rosuvastatin ( 29 ). It is known that ABCC2 ( 11 ) and BSEP ( 30 ) are both regulated by FXR.…”

Section: Discussionmentioning

confidence: 99%

The farnesoid X receptor -1G>T polymorphism influences the lipid response to rosuvastatin

Lui

Tam

et al. 2012

Journal of Lipid Research

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This article is available online at http://www.jlr.org that FXR activation is benefi cial in situations of energy excess, such as obesity and diabetes, and FXR agonists are being evaluated in preclinical studies for treating diabetes and metabolic disorders ( 2, 3 ). Although FXR functions as a bile acid receptor, studies have identifi ed that FXR also regulates multiple drug metabolizing enzyme or drug transporter genes by binding to FXR response elements and promoting transcription of target genes, suggesting that FXR may play an important role in determining the pharmacokinetics and pharmacodynamics of numerous drugs ( 4 ).Recent pharmacogenetic studies have demonstrated that drug transporters, in particular the solute carrier organic anion transporter family, member 1B1 (SLCO1B1) and ATP-binding cassette, subfamily G, member 2 (ABCG2), play an important role in determining the pharmacokinetics and pharmacodynamics of statins ( 5-7 ). It is known that the tissue protein expression of drug transporters is highly variable between individuals and that these interindividual variations in transporter expression may result in variabilities in lipid response to statins ( 4 ). Loss of function single nucleotide polymorphisms (SNP) in the coding region of the SLCO1B1 and ABCG2 genes were associated with altered statin exposure and lipid-lowering effects ( 5-7 ), but these SNPs did not appear to affect overall protein expression ( 4,8 ). Instead, the decreased transport activity of SLCO1B1 and ABCG2 associated with these SNPs is thought to result from membrane-traffi cking defects ( 4, 9, 10 ).FXR regulates several drug transporters involved in statin disposition, including SLCO1B1, SLCO1B3, sodiumtaurocholate cotransporting polypeptide (NTCP), and The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily, which is activated by bile acids. Activation of FXR leads to altered expression of many genes responsible for bile acid and lipid and glucose metabolism and transport, resulting in decreased intracellular bile acid concentrations and reduced plasma glucose and triglyceride levels ( 1, 2 ). Current evidence suggests

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Biliary efflux transporters involved in the clearance of rosuvastatin in sandwich culture of primary rat hepatocytes

Cited by 33 publications

References 29 publications

Hepatic Basolateral Efflux Contributes Significantly to Rosuvastatin Disposition I: Characterization of Basolateral Versus Biliary Clearance Using a Novel Protocol in Sandwich-Cultured Hepatocytes

Hepatic Basolateral Efflux Contributes Significantly to Rosuvastatin Disposition I: Characterization of Basolateral Versus Biliary Clearance Using a Novel Protocol in Sandwich-Cultured Hepatocytes

Interindividual Variability in Hepatic Expression of the Multidrug Resistance-Associated Protein 2 (MRP2/ABCC2): Quantification by Liquid Chromatography/Tandem Mass Spectrometry

The farnesoid X receptor -1G>T polymorphism influences the lipid response to rosuvastatin

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