BioIVT, which provides research models and services for drug development, recently announced that its research into the mechanisms involved in cholestatic drug-induced liver injury (DILI) has been published in Applied In Vitro Toxicology
“To accurately predict the risk of cholestatic DILI, an in vitro model must incorporate the complete bile acid homeostasis mechanism,” explained Graham Dyck, director of marketing, ADME-Tox, BioIVT.
BioIVT has developed a C-DILI assay to integrate direct and adaptive effects of a drug, including BSEP inhibition, basolateral efflux inhibition, and FXR (farnesoid X receptor) antagonism using a human hepatocyte system.
“Pharmaceutical companies are using the C-DILI Assay in their screening and drug development processes to assess hepatotoxicity potential of their lead compounds,” Dyck explained.
BioIVT Study Director and lead author Dr. Jonathan Jackson said it is well established that bile acid homeostasis is critical in assessing cholestatic liver injury in humans. As he explained, conventional methods to predict cholestatic drug induced liver injury (DILI) assess the potential of a compound to inhibit BSEP, a hepatic transporter responsible for biliary excretion of bile acids.
“However, in clinical practice, in vitro BSEP IC50 concentrations are not well correlated with in vivo cholestatic DILI severity,” he told us. “There are approved drugs which show significant BSEP inhibition in in vitro studies but for which there are no reported cases of liver injury or cases are extremely rare.”
The research shows that when treated with BSEP inhibitors, sandwich-cultured human hepatocytes (SCHH) respond to the increased intracellular concentrations of bile acids by activating FXR.
FXR is a nuclear receptor that down-regulates hepatic synthesis of bile acids and up-regulates basolateral transporters, which also can excrete bile acids, Jackson explained.
“For the first time our study demonstrated the ‘link’ between BSEP inhibition and FXR, a master regulator of bile acid homeostasis, and demonstrates the ‘adaptive response’ that can occur if bile acid concentrations are elevated as a direct result of BSEP inhibition,” he said.
Jackson added, “This research introduces a new paradigm suggesting BSEP inhibition alone will not lead to bile acid-induced liver injury that an additional insult is required such as interfering with FXR function.”
Source: Applied In Vitro Toxicology
Cholestatic Drug Induced Liver Injury: A Function of Bile Salt Export Pump Inhibition and Farnesoid X Receptor Antagonism
Authors: Jonathan P. Jackson, Kimberly M. Freeman, Robert L. St. ClaireIII, Chris B. Black, and Kenneth R. Brouwer