Organic Anion Transporting Polypeptide 1B1: a Genetically Polymorphic Transporter of Major Importance for Hepatic Drug Uptake

Niemi, Mikko; Pasanen, Marja K.; Neuvonen, Pertti J.

doi:10.1124/pr.110.002857

Cited by 550 publications

(593 citation statements)

References 228 publications

(347 reference statements)

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“…All individuals included in the study were genotyped for the frequently occurring nonsynonymous polymorphisms SLCO1B1 c.521T > C and SLCO1B1 c.388A > G [12,13]. Assessment for the c.SLCO1B1 388A > G was performed using a predeveloped TaqMan SNP detection assay from Applied Biosystems (Darmstadt, Germany).…”

Section: Genotypingmentioning

confidence: 99%

“…In 2001, Tirona et al [12] identified several polymorphisms localized in the coding region of the gene to be associated with impaired transport function. In particular, the frequent single nucleotide polymorphism (SNP) SLCO1B1 c.521C results in significant changes in pharmacokinetics (increased area under the curve) of several statins (pravastatin, atorvastatin, rosuvastatin and simvastatin) in healthy volunteers (summarized in the study of Niemi et al [13]). The assumption that OATP1B transporters are important in pharmacokinetics of statins is indirectly supported by findings showing that the frequently occurring functionimpairing allele SLCO1B1 c.521C is most predictive for extrahepatic adverse events (myopathy, rhabdomyolysis) of simvastatin therapy [14,15].…”

Section: Introductionmentioning

confidence: 99%

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Function-impairing polymorphisms of the hepatic uptake transporter SLCO1B1 modify the therapeutic efficacy of statins in a population-based cohort

Schwabedissen

Albers²,

Baumeister³

et al. 2015

Pharmacogenetics and Genomics

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Background The efficacy of statins, which are used commonly in primary and secondary prevention of cardiovascular diseases, shows a wide range of interindividual variability. Genetic variants of OATP1B1, a hepatic uptake transporter, can modify access of statins to its therapeutic target, thereby potentially altering drug efficacy. We studied the impact of genetic variants of OATP1B1 on the lipid-lowering efficacy of statins in a population-based setting. Materials and methodsThe basis of the analysis was the Study of Health in Pomerania, a cohort of 2732 men and women aged 20-81 years. Included in the statistical analysis to evaluate the impact of OATP1B1 on therapeutic efficacy of statins were 214 individuals diagnosed with dyslipidaemia during initial recruitment and receiving statins during the 5-year follow-up.Results Analysing the impact of the OATP1B1 genotype, we observed a trend for lower statin-induced total cholesterol reduction in carriers of the SLCO1B1 512C variant. Restricting the analysis to patients receiving simvastatin, pravastatin, lovastatin and fluvastatin indicated a statistically significant association of the OATP1B1 genotype on lipid parameters at the 5-year follow-up. No such effect was observed for atorvastatin. Calculation of achievement of treatment goals according to the NCEP-ATPIII guidelines showed a lower rate of successful treatment when harbouring the mutant allele for patients taking simvastatin (46.7 vs. 73.9%). A similar trend was observed for pravastatin (34.4 vs. 70.4%).Conclusion Genetic variants of OATP1B1 leading to impaired hepatic uptake of statins translated into reduced drug efficacy in a population-based cohort.

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Section: Genotypingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Function-impairing polymorphisms of the hepatic uptake transporter SLCO1B1 modify the therapeutic efficacy of statins in a population-based cohort

Schwabedissen

Albers²,

Baumeister³

et al. 2015

Pharmacogenetics and Genomics

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“…Hence, the SLCO1B1 polymorphism c.521T>C appears to be the most thoroughly documented polymorphism in the area of drug transporter pharmacogenetics. Besides statins, a considerable number of additional drugs such as for example antidiabetics, anticancer drugs, immunosuppressants, sartans or antibiotics have been found to display pharmacokinetic differences for different OATP1B1 phenotypes [8,60,147].…”

Section: Oatp1b1 (Scl1b1)mentioning

confidence: 99%

Pharmacogenetics of Drug Transporters in the Enterohepatic Circulation

Stieger

Meier

2011

Pharmacogenomics

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This article summarizes the impact of the pharmacogenetics of drug transporters expressed in the enterohepatic circulation on the pharmacokinetics and pharmacodynamics of drugs. The role of pharmacogenetics in the function of drug transporter proteins in vitro is now well established and evidence is rapidly accumulating from in vivo pharmacokinetic studies, which suggests that genetic variants of drug transporter proteins can translate into clinically relevant phenotypes. However, a large amount of conflicting information on the clinical relevance of drug transporter proteins has so far precluded the emergence of a clear picture regarding the role of drug transporter pharmacogenetics in medical practice. This is very well exemplified by the case of P-glycoprotein (MDR1, ABCB1). The challenge is now to develop pharmacogenetic models with sufficient predictive power to allow for translation into drug therapy. This will require a combination of pharmacogenetics of drug transporters, drug metabolism and pharmacodynamics of the respective drugs.

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“…Despite the title, OATP substrates are not limited to organic anions, but also include cations as well as neutral and zwitterionic compounds (Niemi et al, 2011). The three hepatic OATPs have substantial overlapping substrate specificities and mediate the sodium ion co-transport of various organic agents including organic dyes, bile salts, steroid conjugates and thyroid hormones.…”

Section: Introductionmentioning

confidence: 99%

“…Biliary excretion is an important route for the elimination of many drugs and/or their metabolites (Rollins and Klaassen, 1979). Since a big part of intact drug molecules and their metabolites are excreted through bile (Niemi et al, 2011), during pharmacokinetic studies, evaluation of biliary excretion of drugs is essential as it can impact on the drug half-life and drug-drug interactions, and may complicate the pharmacokinetics due to the possibility of enterohepatic circulation.…”

Section: Introductionmentioning

confidence: 99%

Effect of OATP-binding on the prediction of biliary excretion

Sharifi

Ghafourian

2016

Xenobiotica

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Article (Accepted Version) http://sro.sussex.ac.uk Sharifi, Mohsen and Ghafourian, Taravat (2017) Effect of OATP-binding on the prediction of biliary excretion. Xenobiotica, 47 (7). pp. [614][615][616][617][618][619][620][621][622][623][624][625][626][627][628][629][630][631] This version is available from Sussex Research Online: http://sro.sussex.ac.uk/64120/ This document is made available in accordance with publisher policies and may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the URL above for details on accessing the published version. Copyright and reuse:Sussex Research Online is a digital repository of the research output of the University.Copyright and all moral rights to the version of the paper presented here belong to the individual author(s) and/or other copyright owners. To the extent reasonable and practicable, the material made available in SRO has been checked for eligibility before being made available.Copies of full text items generally can be reproduced, displayed or performed and given to third parties in any format or medium for personal research or study, educational, or not-for-profit purposes without prior permission or charge, provided that the authors, title and full bibliographic details are credited, a hyperlink and/or URL is given for the original metadata page and the content is not changed in any way. The results indicated that incorporation of predicted OATP inhibition improves accuracy of biliary excretion models. The best result was obtained from a simple regression tree that used predicted OATP1B1 percentage inhibition at the root node of the tree. Effect of OATP-binding on the prediction of biliary excretion

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Organic Anion Transporting Polypeptide 1B1: a Genetically Polymorphic Transporter of Major Importance for Hepatic Drug Uptake

Cited by 550 publications

References 228 publications

Function-impairing polymorphisms of the hepatic uptake transporter SLCO1B1 modify the therapeutic efficacy of statins in a population-based cohort

Function-impairing polymorphisms of the hepatic uptake transporter SLCO1B1 modify the therapeutic efficacy of statins in a population-based cohort

Pharmacogenetics of Drug Transporters in the Enterohepatic Circulation

Effect of OATP-binding on the prediction of biliary excretion

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