Comprehensive Evaluation of Bile Acid Homeostasis in Human Hepatocyte Co-Culture in the Presence of Troglitazone, Pioglitazone and Acetylsalicylic Acid

Interruption of bile acid (BA) homeostasis has been hypothesized for a variety of liver diseases and for drug-induced liver injury (DILI). Consequently, BA is gaining increasing prominence as a potential biomarker. The objective of this work was to evaluate the effect of troglitazone (TZN, associated with severe DILI), pioglitazone (PZN, rarely associated with DILI), and acetylsalicylic acid (ASA, or aspirin, not associated with DILI), on the in-vitro BA homeostasis in hepatocytes co-cultured with non-parenchymal cells by monitoring the disposition of 36 BAs. Cells were supplemented with 2.5 µM D4-cholic acid (D4-CA), D4-chenodeoxycholic acid (D4-CDCA), D4-lithocholic acid (D4-LCA), D4-deoxycholic acid (D4-DCA), D4-ursodeoxycholic acid (D4-UDCA) and hyodeoxycholic acid (HDCA). Concentration-time profiles of BAs were used to determine AUC from supernatant, lysate or bile compartments, in the presence or absence of TZN, PZN or ASA. When applicable, IC50 describing depletion of individual BAs was calculated,...