Intravital Multiphoton Microscopy with Fluorescent Bile Salts in Rats as an In Vivo Biomarker for Hepatobiliary Transport Inhibition

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Jennifer C RyanKenneth W Dunn

Abstract

The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it mediates the elimination of monovalent bile salts into the bile. Inhibition of BSEP is considered a susceptibility factor for drug-induced liver injury that often goes undetected during nonclinical testing. Although in vitro assays exist for screening BSEP inhibition, a reliable and specific method for confirming Bsep inhibition in vivo would be a valuable follow up to a BSEP screening strategy, helping to put a translatable context around in vitro inhibition data, incorporating processes such as metabolism, protein binding, and other exposure properties that are lacking in most in vitro BSEP models. Here, we describe studies in which methods of quantitative intravital microscopy were used to identify dose-dependent effects of two known BSEP/Bsep inhibitors, 2-[4-[4-(butylcarbamoyl)-2-[(2,4-dichlorophenyl)sulfonylamino]phenoxy]-3-methoxyphenyl]acetic acid (AMG-009) and bosentan, on hepatocellular transport of the fluorescent bile salts cholylglycyl amidofluorescein and cholyl-lysyl-fluorescein in rats. Results of these studies demonstrate that the intravital microscopy approach is capable of detecting Bsep inhibition at drug doses w...Continue Reading

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Citations

Apr 11, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Qingcheng MaoJoanne Wang
Mar 9, 2021·Frontiers in Bioengineering and Biotechnology·Ravikumar VaghelaMaximilian Hessenauer
Mar 9, 2021·American Journal of Physiology. Renal Physiology·Kenneth W DunnPierre C Dagher
Oct 7, 2020·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Manisha NautiyalMerrie Mosedale

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