Preclinical/Animal Transporters

Bsep - cynomolgus monkey

Human BSEP (Bile Salt Export Pump, ABCB11) is a unidirectional, ATP-dependent efflux transporter that plays an important role in the elimination of bile salts from the hepatocyte into the bile canaliculi for export into the gastrointestinal tract. It is almost exclusively expressed in the liver, with much lower levels reported in the kidney. BSEP mediates the hepatic excretion of monovalent conjugated bile acids. [1] It is predominantly of relevance to hepatotoxicity, as BSEP inhibition by a drug and/or its metabolites can result in the build-up of bile salts in the liver, which can lead to cholestasis and drug-induced liver injury (DILI). Compared to other drug transporters there are only few identified drug substrates and inhibitors of BSEP; thus, its involvement in drug-drug interactions (DDI) is somewhat limited. The relevance of in vitro BSEP inhibition as a predictor of clinical outcomes is not clearly established, but whenever cholestatic liver injury is observed in clinical or preclinical trials, characterization of BSEP interactions should be considered.
The cynomolgus monkey (Macaca fascicularis) as a nonhuman primate is generally considered a superior preclinical model of human drug disposition, and has thus become the most important close-to-human preclinical species in drug development. Interspecies differences in expression of the hepatobiliary transporters (BSEP, MATE1, MRP3, MRP4, NTCP, and OCT1) were quantified by liquid chromatography tandem mass spectrometry and compared in liver tissue and hepatocytes of human, dog, cynomolgus monkey, and rat. In all the species, BSEP/Bsep showed high relative expression in the sinusoidal and canalicular membrane [2]. The protein expression of BSEP/Bsep was similar in human, male beagle dogs, cynomolgus monkeys, Sprague Dawley rats, and Wistar rats [2,3].

1.    Cheng, Xingguo, David Buckley, and Curtis D. Klaassen. "Regulation of hepatic bile acid transporters Ntcp and Bsep expression." Biochemical pharmacology 74.11 (2007): 1665-1676.
2.    Wang, Li, et al. "Interspecies variability in expression of hepatobiliary transporters across human, dog, monkey, and rat as determined by quantitative proteomics." Drug Metabolism and Disposition 43.3 (2015): 367-374.
3.    Bleasby, K., et al. "Expression profiles of 50 xenobiotic transporter genes in humans and pre-clinical species: a resource for investigations into drug disposition." Xenobiotica 36.10-11 (2006): 963-988.

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