Abstract
Troglitazone (TGZ) caused delayed, life-threatening drug-induced liver injury (DILI) in some patients, but was not hepatotoxic in rats. This study investigated altered bile acid (BA) homeostasis as a mechanism of TGZ hepatotoxicity using a systems pharmacology model incorporating drug/metabolite disposition, BA physiology/pathophysiology, hepatocyte life cycle, and liver injury biomarkers. In the simulated human population, TGZ (200–600mg/day×6months) resulted in delayed increases in serum ALT>3× ULN in 0.3–5.1% of the population with concomitant bilirubin elevations>2× ULN in 0.3–3.6%. In contrast, pioglitazone (15–45mg/day×6months) did not elicit hepatotoxicity, consistent with clinical data. TGZ was not hepatotoxic in the simulated rat population. In summary, mechanistic modeling based only on BA effects accurately predicted the incidence, delayed presentation, and species differences in TGZ hepatotoxicity, and the relative liver safety of pioglitazone. Systems pharmacology models integrating physiology and experimental data can evaluate DILI mechanisms and may be useful to predict hepatotoxic potential of drug candidates.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
