Association of genetic polymorphism in ABCC2 with hepatic multidrug resistance-associated protein 2 expression and pravastatin pharmacokinetics

Niemi, Mikko; Arnold, Katja A.; Backman, Janne T.; Pasanen, Marja K.; Gödtel-Armbrust, Ute; Wojnowski, Leszek; Zanger, Ulrich M.; Neuvonen, Pertti J.; Eichelbaum, Michel; Kivistö, Kari T.; Lang, Thomas

doi:10.1097/01.fpc.0000230422.50962.91

Cited by 100 publications

(75 citation statements)

References 26 publications

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“…3,[21][22][23] Similarly, in vitro studies of multidrug resistanceassociated protein 2 have shown that this protein transports a number of statins, 24 but in vivo pharmacogenomic evidence is inconclusive and limited to two small pharmacokinetic studies using pravastatin; these studies obtained contrasting results. 25,26 In contrast, the c.421C4A SNP in ABCG2 has been shown to alter the in vivo pharmacokinetics of both rosuvastatin 27,28 and atorvastatin, 27 although not pitavastatin 29 or pravastatin. 26 Both multidrug resistanceassociated protein 2 and breast cancer resistance protein are reviewed elsewhere by Ieiri et al 19 and although it is accepted that these and other transporters, both intestinal and hepatic, may play a role in statin disposition, this review will focus exclusively on OATP1B1, an hepatic influx transporter that is becoming increasing linked with differences in response to statin therapy.…”

Section: Hepatic Transportersmentioning

confidence: 99%

The influence of SLCO1B1 (OATP1B1) gene polymorphisms on response to statin therapy

et al. 2009

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Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are well established in the treatment of hypercholesterolaemia and the prevention of coronary artery disease. Despite this, there is wide interindividual variability in response to statin therapy, in terms of both lipidlowering and adverse drug reactions. The major site of statin action is within hepatocytes and recent interest has focussed on genetic variation in hepatic influx and efflux transporters for their potential to explain these differences. In this review we explore current literature regarding the pharmacokinetic and pharmacodynamic influence of the common c.388A4G and c.521T4C single-nucleotide polymorphisms (SNPs) within the solute carrier organic anion transporter 1B1 (SLCO1B1) gene, encoding the organic anion transporter polypeptide 1B1 (OATP1B1) influx transporter. We discuss their potential to predict the efficacy of statin therapy and the likelihood that patients will experience adverse effects.

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Section: Hepatic Transportersmentioning

confidence: 99%

The influence of SLCO1B1 (OATP1B1) gene polymorphisms on response to statin therapy

et al. 2009

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“…17 In addition, the synonymous mutation 1446C4G was associated with increased hepatic mRNA expression resulting in low C max and area under the plasma concentration time curve (AUC) values for pravastatin. 18 A haplotype-based approach to identifying the genetic variation underlying drug response and disposition as well as common diseases has been proposed. [19][20][21][22] The International HapMap Project has characterized the pattern of haplotype structure and linkage disequilibrium (LD) across the human genome to facilitate genome-wide association studies.…”

Section: Introductionmentioning

confidence: 99%

Association study of genetic polymorphisms of drug transporters, SLCO1B1, SLCO1B3 and ABCC2, in African-Americans, Hispanics and Caucasians and olmesartan exposure

et al. 2012

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It has been reported that organic anion-transporting polypeptide (OATP) 1B1, OATP1B3 and multidrug resistance-associated protein 2 are involved in the hepatobiliary transport of olmesartan. We investigated the association of SLCO1B1, SLCO1B3 and ABCC2 polymorphisms with the pharmacokinetics of olmesartan. We sequenced all exons, exon-intron junctions and the 5 0 and 3 0 flanking regions of the three genes in 115 individuals from African-American, Hispanic and Caucasian populations who had participated in our clinical studies. A total of 348 single-nucleotide polymorphisms (SNPs) were identified with a minor allele frequency of X0.01 in at least one population; 132 SNPs were detected in SLCO1B1, 130 in SLCO1B3 and 86 in ABCC2. We characterized the linkage disequilibrium (LD) and haplotypes shared across the populations and then evaluated the association between the haplotypes and the pharmacokinetics of olmesartan. Seven inter-ethnic LD blocks were observed in SLCO1B1, while three in SLCO1B3 and four in ABCC2. Although extensive variability in the sequences of SLCO1B1, SLCO1B3 and ABCC2 existed across the three populations, there was no remarkable difference in any pharmacokinetic parameters of olmesartan between subjects with and without any major haplotypes in the three transporter genes we tested.

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“…12 Rare ABCC2 variants such as 1446C4G, 3563T4A and 4544G4A were described to be associated with higher mRNA and protein expression in liver, respectively. 13,14 Currently, it is not exactly known how and on which stage genetic variants interfere with the gene expression of ABCC2. Considering the full-length cDNA of ABCC2, we conducted different in vitro approaches to systematically follow the molecular effect of the most common SNPs (À24C4T, 1249G4A and 3972C4T) in Caucasians.…”

Section: Introductionmentioning

confidence: 99%

Impact of ABCC2 haplotypes on transcriptional and posttranscriptional gene regulation and function

et al. 2010

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ABCC2 (MRP2) is an important export pump, expressed at tissue barriers. The genetic variants À24C4T, 1249G4A and 3972C4T are leading to inter-individual differences of bioavailability of various endogenous and exogenous compounds. Considering ABCC2 haplotypes, we investigated DNA-protein binding properties, mRNA secondary structure, mRNA stability, protein expression and transport activity in various cell lines and analyzed the bioavailability of talinolol in 24 healthy Caucasian volunteers; À24C4T had no clear influence on DNA-protein binding and the mRNA stability did not differ significantly. In transfected HEK293T/17 cells, haplotypes H9 (CGT), H10 (TGC) and H12 (TGT) had significantly lower protein expression, whereas H2 (CAC) exhibited significantly increased protein expression compared to the wild type (H1, CGC): 32.7 ± 8.8, 73.1 ± 6.3; 44.0 ± 15.5 and 115.2±8.2%, respectively. This corresponded with efflux rates of the fluorescent dye glutathione-methylfluorescein in vitro and by trend with talinolol bioavailability in vivo. In conclusion our results show a haplotypedependent influence on transport capacity of ABCC2, which seems to be mainly based on posttranscriptional modification of protein expression rather than transport rates.

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Association of genetic polymorphism in ABCC2 with hepatic multidrug resistance-associated protein 2 expression and pravastatin pharmacokinetics

Cited by 100 publications

References 26 publications

The influence of SLCO1B1 (OATP1B1) gene polymorphisms on response to statin therapy

The influence of SLCO1B1 (OATP1B1) gene polymorphisms on response to statin therapy

Association study of genetic polymorphisms of drug transporters, SLCO1B1, SLCO1B3 and ABCC2, in African-Americans, Hispanics and Caucasians and olmesartan exposure

Impact of ABCC2 haplotypes on transcriptional and posttranscriptional gene regulation and function

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