Identification of reversible OATP1B1 and time-dependent CYP3A4 inhibition as the major risk factors for drug-induced cholestasis (DIC)

• Published in: Archives of toxicology Vol. 98; no. 10; pp. 3409 - 3424
• Main Authors: Kastrinou-Lampou, Vlasia, Rodríguez-Pérez, Raquel, Poller, Birk, Huth, Felix, Gáborik, Zsuzsanna, Mártonné-Tóth, Beáta, Temesszentandrási-Ambrus, Csilla, Schadt, Heiko S., Kullak-Ublick, Gerd A., Arand, Michael, Camenisch, Gian
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.10.2024; Springer Nature B.V
• Subjects: Annotations; Bile; Bile acids; Biomedical and Life Sciences; Biomedicine; Cholestasis; Classification systems; Cytochrome P450; Cytochromes P450; Environmental Health; Gallbladder diseases; Homeostasis; Human performance; Injury prevention; Liver; Occupational Medicine/Industrial Medicine; Organ toxicity and Mechanisms; Organic anion transporting polypeptide; Pharmacology/Toxicology; Polypeptides; Risk assessment; Risk factors; Statistical methods; Statistics; Time dependence; Drug-induced cholestasis; Cholestatic DILI; Bile acids; CYP3A4; OATP1B1
• ISSN: 0340-5761; 1432-0738; 1432-0738
• DOI: 10.1007/s00204-024-03794-3

Hepatic bile acid regulation is a multifaceted process modulated by several hepatic transporters and enzymes. Drug-induced cholestasis (DIC), a main type of drug-induced liver injury (DILI), denotes any drug-mediated condition in which hepatic bile flow is impaired. Our ability in translating preclinical toxicological findings to human DIC risk is currently very limited, mainly due to important interspecies differences. Accordingly, the anticipation of clinical DIC with available in vitro or in silico models is also challenging, due to the complexity of the bile acid homeostasis. Herein, we assessed the in vitro inhibition potential of 47 marketed drugs with various degrees of reported DILI severity towards all metabolic and transport mechanisms currently known to be involved in the hepatic regulation of bile acids. The reported DILI concern and/or cholestatic annotation correlated with the number of investigated processes being inhibited. Furthermore, we employed univariate and multivariate statistical methods to determine the important processes for DILI discrimination. We identified time-dependent inhibition (TDI) of cytochrome P450 (CYP) 3A4 and reversible inhibition of the organic anion transporting polypeptide (OATP) 1B1 as the major risk factors for DIC among the tested mechanisms related to bile acid transport and metabolism. These results were consistent across multiple statistical methods and DILI classification systems applied in our dataset. We anticipate that our assessment of the two most important processes in the development of cholestasis will enable a risk assessment for DIC to be efficiently integrated into the preclinical development process.