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Transport proteins control the selective transport of molecules across membranes and are required for the proper function of cells. With regard to pharmacology, drug transport proteins are involved in the disposition of all drugs and are important determinants of whether drugs will reach their therapeutic targets. Modulation of the function of these drug transporters by other drugs can lead to serious clinical disorders or severe drug-drug interactions. We are mainly working with the hepatocyte-specific organic anion transporting polypeptides OATP1B1 and OATP1B3 which have been shown to mediate the uptake of numerous drugs into hepatocytes. These two transporters are closely related and have a broad and overlapping substrate specificity. Interestingly, inhibitors or modulators of these OATPs act in a substrate-dependent way which can lead to inhibition or stimulation of substrate uptake. Recently we could demonstrate that OATP1B3 interacts with other transporters in human hepatocytes. We currently investigate which transporters interact and what the functional consequence of these interactions is in human hepatocytes. Another research focus is how the function of the sodium-dependent bile acid transporter, NTCP, is affected by amino acid replacements at conserved and non-conserved positions. The hypothesis we are testing is that amino acid replacements at conserved positions likely have either no effect or are detrimental, thus representing a toggle position. However, when amino acids are replaced with every possible other amino acid at non-conserved positions, this likely results in a gradual inhibition or stimulation and therefore represents a rheostat position. Eventually, these results should allow to predict such changes and are directed towards improving precision medicine. With respect to toxicology with have ongoing collaborations to characterize transporter-mediated disposition of perfluorinated compounds that are environmentally stable and have sometimes very long half-lives in humans.
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ASPET 2024 Annual Meeting Abstract - Drug Metabolism and Disposition (DMD) (2024)
Wanjun Han,Zheyue Bo, Ting Liang, Han Liu,Lanjing Li, Zhening Guo, Ru Huan,Bruno Hagenbuch,Chunshan Gui
Molecular pharmaceuticsno. 2 (2024): 854-863
RSC MEDICINAL CHEMISTRYno. 5 (2023): 890-898
British Journal of Pharmacologyno. S2 (2023): S374-S469
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS (2023)
crossref(2023)
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