OATP2B1 - the underrated member of the Organic Anion Transporting Polypeptide Family of drug transporters?

(1) Background: Hydroxychloroquine is used to treat malaria and autoimmune diseases, and its potential use against COVID-19 is currently under investigation. Thus far, information on interactions of hydroxychloroquine with drug transporters mediating drug-drug interactions is limited. We assessed the inhibition of important efflux (P-glycoprotein (P-gp), breast cancer resistance protein (BCRP)) and uptake transporters (organic anion transporting polypeptide (OATP)-1B1, OATP1B3, OATP2B1) by hydroxychloroquine, tested its P-gp and BCRP substrate characteristics, and evaluated the induction of pharmacokinetically relevant genes regulated by the nuclear pregnane X (PXR) (CYP3A4, ABCB1) and aryl hydrocarbon receptor (AhR) (CYP1A1, CYP1A2). (2) Methods: Transporter inhibition was evaluated in transporter over-expressing cell lines using fluorescent probe substrates. P-gp and BCRP substrate characteristics were assessed by comparing growth inhibition of over-expressing and parental cell lines. Possible mRNA induction was analysed in LS180 cells by quantitative real-time PCR. (3) Results: Hydroxychloroquine did not inhibit BCRP or the OATPs tested but inhibited P-gp at concentrations exceeding 10 µM. P-gp overexpressing cells were 5.2-fold more resistant to hydroxychloroquine than control cells stressing its substrate characteristics. Hydroxychloroquine did not induce genes regulated by PXR or AhR. (4) Conclusions: This is the first evidence that hydroxychloroquine’s interaction potential with drug transporters is low, albeit bioavailability of simultaneously orally administered P-gp substrates might be increased by hydroxychloroquine.

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Faculty Opinions recommendation of Naringin is a major and selective clinical inhibitor of organic anion-transporting polypeptide 1A2 (OATP1A2) in grapefruit juice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1120234.576396 ◽

2008 ◽

Author(s):

Pierre Wallemacq

Keyword(s):

Grapefruit Juice ◽

Organic Anion ◽

Organic Anion Transporting Polypeptide

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Faculty Opinions recommendation of Oligomerization study of human organic anion transporting polypeptide 1B1.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727097922.793532705 ◽

2017 ◽

Author(s):

Allan Wolkoff

Keyword(s):

Organic Anion ◽

Organic Anion Transporting Polypeptide

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Liver and Statins: A Critical Appraisal of the Evidence

Current Medicinal Chemistry ◽

10.2174/0929867325666180327095441 ◽

2019 ◽

Vol 25 (42) ◽

pp. 5835-5846 ◽

Cited By ~ 6

Author(s):

Anna Licata ◽

Antonina Giammanco ◽

Maria Giovanna Minissale ◽

Salvatore Pagano ◽

Salvatore Petta ◽

...

Keyword(s):

Adverse Events ◽

Association Studies ◽

Organic Anion ◽

Genome Wide Association Studies ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Organic Anion Transporting Polypeptide ◽

Treatment And Prevention ◽

Genome Wide ◽

Underlying Mechanisms

Adverse drug reactions (ADRs) represent an important cause of morbidity and mortality worldwide. Statins are a class of drugs whose main adverse effects are drug-induced liver injury (DILI) and myopathy. Some of these may be predictable, due to their pharmacokinetic and pharmacodynamic properties, while others, unfortunately, are idiosyncratic. Genetic factors may also influence patient susceptibility to DILI and myopathy in the case of statins. This review will first discuss the role of statins in cardiovascular disease treatment and prevention and the underlying mechanisms of action. Furthermore, to explore the susceptibility of statin-induced adverse events such as myopathy and hepatotoxicity, it will then focus on the recent Genome-Wide Association Studies (GWAS) concerning the transporter genes, Cytochrome P450 (CYP), organic anion-transporting polypeptide (OATP) and ABCB1 and ABCC1, which seem to play a role in the development of clinically relevant adverse events. Finally, we appraise the evidence for and against the use of statins in metabolic syndrome and in HCV-infected patients, in terms of their safety and efficacy in cardiovascular events.

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Minireview: Thyroid Hormone Transporters: The Knowns and the Unknowns

Molecular Endocrinology ◽

10.1210/me.2010-0095 ◽

2011 ◽

Vol 25 (1) ◽

pp. 1-14 ◽

Cited By ~ 256

Author(s):

W. Edward Visser ◽

Edith C. H. Friesema ◽

Theo J. Visser

Keyword(s):

Thyroid Hormone ◽

Organic Anion ◽

Psychomotor Retardation ◽

Cellular Level ◽

Monocarboxylate Transporter ◽

Causative Role ◽

Organic Anion Transporting Polypeptide ◽

Neurological Abnormalities ◽

Knockout Animals

The effects of thyroid hormone (TH) on development and metabolism are exerted at the cellular level. Metabolism and action of TH take place intracellularly, which require transport of the hormone across the plasma membrane. This process is mediated by TH transporter proteins. Many TH transporters have been identified at the molecular level, although a few are classified as specific TH transporters, including monocarboxylate transporter (MCT)8, MCT10, and organic anion-transporting polypeptide 1C1. The importance of TH transporters for physiology has been illustrated dramatically by the causative role of MCT8 mutations in males with psychomotor retardation and abnormal serum TH concentrations. Although Mct8 knockout animals have provided insight in the mechanisms underlying parts of the endocrine phenotype, they lack obvious neurological abnormalities. Thus, the pathogenesis of the neurological abnormalities in males with MCT8 mutations is not fully understood. The prospects of identifying other transporters and transporter-based syndromes promise an exciting future in the TH transporter field.

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