BioIVT, a leading provider of research models and services for drug development, today announced its research into the mechanisms involved in cholestatic drug-induced liver injury (DILI) has been published in Applied In Vitro Toxicology.
DILI is one of the primary causes of drug development failures. As a result, sponsors endeavor to identify new drug candidates with a high DILI risk early in the development process. Early cholestatic DILI screening efforts historically focused on a compound's potential to inhibit BSEP, a protein responsible for excretion of bile acids from the liver. However, BSEP inhibition potency is not always correlated with DILI suggesting that other mechanisms may be involved. BioIVT researchers demonstrated that BSEP inhibition ''triggers'' the activation of compensatory mechanisms that suppress bile acid synthesis and increase bile acid excretion through routes other than BSEP, thereby preventing hepatotoxicity.
"Cholestatic DILI is known to have a weak association with BSEP inhibition," said BioIVT Study Director and Lead Author Jonathan Jackson, PhD. "For the first time, our study demonstrated the 'link' between BSEP inhibition and FXR, a master regulator of bile acid homeostasis. FXR activation by BSEP inhibition may explain the weak concordance between BSEP inhibition potency and cholestatic DILI incidence. Many compounds inhibit BSEP; however, liver cells can compensate for the resulting increase in bile acid concentration. In fact, clinical observations show that increases in circulating bile acids are not always associated with DILI. Our discovery suggests a new paradigm is required to accurately predict a drug candidate's cholestatic DILI potential, and new methods are needed, such as our C-DILI Assay."
The C-DILI Assay integrates cellular compensatory mechanisms with BSEP inhibition. Because the assay accounts for the adaptive response observed in liver cells, it has been shown to have high in vitro-in vivo correlation among compounds known to have a risk of DILI. As part of their screening and drug development processes, pharmaceutical companies use the C-DILI Assay to assess hepatotoxicity potential of their lead compounds.
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