Drug-induced liver injury (DILI) is one of the most common adverse reactions to drugs or other xenobiotics, approximated to occur in 1/100 patients during hospitalization. DILI has various clinical manifestations, which may range from asymptomatic liver test results to lethal complications. Among these, drug-induced cholestasis (DIC), while often considered low severity, frequently develops into a chronic condition. Therefore, its accurate risk assessment preclinically is especially important.
In DIC, hepatic bile flow is impaired via a complex process modulated by several hepatic transporters and enzymes. Preclinical toxicological studies often do not predict human DIC efficiently enough due to important interspecies differences. The complexity of bile acid homeostasis also poses a challenge when developing and applying in vitro or in silico models for clinical DIC risk assessment.
In these new studies, the major risk factors driving DIC were identified as time-dependent inhibition (TDI) of cytochrome P450 (CYP) 3A4 and reversible inhibition of the organic anion transporting polypeptide (OATP) 1B1 in a synergistic manner. Based on these two processes, a strategy for DIC risk assessment can be designed and integrated into the preclinical development process. Application of such a quantitative model in the preclinical investigations of DIC is expected to reduce attrition rate in advanced development programs and guide the discovery and development of safer medicines.
RegisterKey Learning Objectives
- Understand the molecular mechanisms involved in drug-induced cholestasis (DIC)
- Discover in vitro assays that can be applied to predict DIC risk
- Learn about a quantitative pre-clinical model for DIC liability prediction and de-risking
