Genetic variants of SLCO1B7 are of relevance for the transport function of OATP1B3-1B7

Schwabedissen, Henriette E. Meyer zu; Seibert, Isabell; Grube, Markus; Alter, Claudio Luca; Siegmund, Werner; Hußner, Janine

doi:10.1016/j.phrs.2020.105155

Cited by 4 publications

(2 citation statements)

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“…Whether OATP1B3-1B7 is of clinical relevance remains to be tested in pharmacogenetic studies. 34 Nuclear factor kappa B (NF-kB) and inflammatory responses Signaling pathways underlying stress-induced regulation of transporters are complex and not well-understood. For instance, in isolated rat blood-brain-barrier (BBB) capillaries, protein levels of efflux transporters were upregulated in response to chronic inflammation, oxidative stress, DNA damage, and seizures.…”

Section: Epigenetic Gene Regulationmentioning

confidence: 99%

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Regulation of Drug Transport Proteins—From Mechanisms to Clinical Impact: A White Paper on Behalf of the International Transporter Consortium

Brouwer

Evers

Hayden

et al. 2022

Clin Pharma and Therapeutics

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Membrane transport proteins are involved in the absorption, disposition, efficacy, and/or toxicity of many drugs. Numerous mechanisms (e.g., nuclear receptors, epigenetic gene regulation, microRNAs, alternative splicing, post-translational modifications, and trafficking) regulate transport protein levels, localization, and function. Various factors associated with disease, medications, and dietary constituents, for example, may alter the regulation and activity of transport proteins in the intestine, liver, kidneys, brain, lungs, placenta, and other important sites, such as tumor tissue. This white paper reviews key mechanisms and regulatory factors that alter the function of clinically relevant transport proteins involved in drug disposition. Current considerations with in vitro and in vivo models that are used to investigate transporter regulation are discussed, including strengths, limitations, and the inherent challenges in predicting the impact of changes due to regulation of one transporter on compensatory pathways and overall drug disposition. In addition, translation and scaling of in vitro observations to in vivo outcomes are considered. The importance of incorporating altered transporter regulation in modeling and simulation approaches to predict the clinical impact on drug disposition is also discussed. Regulation of transporters is highly complex and, therefore, identification of knowledge gaps will aid in directing future research to expand our understanding of clinically relevant molecular mechanisms of transporter regulation. This information is critical to the development of tools and approaches to improve therapeutic outcomes by predicting more accurately the impact of regulation-mediated changes in transporter function on drug disposition and response.Transport proteins of the solute carrier (SLC) and ATP-binding cassette (ABC) superfamilies are widely recognized as key determinants of the absorption, distribution, and excretion of many endogenous compounds and xenobiotics, including drugs, bile acids, hormones, and nutrients, which may thereby directly or indirectly impact medication efficacy and/or safety. Not surprisingly, intersubject variability in drug response due to transporters has been attributed to altered transporter function in organs, such as the intestine, liver, and kidneys. 1,2 Mechanisms of alterations in drug transporter activity have focused primarily on (i) differences in gene expression and/ or protein abundance due to genetic polymorphisms; and (ii) drug-drug interactions (DDIs) predominantly involving direct

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Section: Epigenetic Gene Regulationmentioning

confidence: 99%

“…The result is a protein with 12 transmembrane domains mostly localized in the endoplasmic reticulum. Whether OATP1B3‐1B7 is of clinical relevance remains to be tested in pharmacogenetic studies 34 …”

Section: Mechanisms Of Transporter Regulationmentioning

confidence: 99%