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Systems Pharmacology Modeling Predicts Delayed Presentation and Species Differences in Bile Acid–Mediated Troglitazone Hepatotoxicity
Author(s) -
Yang K,
Woodhead J L,
Watkins P B,
Howell B A,
Brouwer K L R
Publication year - 2014
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2014.158
Subject(s) - troglitazone , pharmacology , liver injury , medicine , drug , bile acid , population , metabolite , alanine transaminase , pharmacokinetics , endocrinology , peroxisome proliferator activated receptor , receptor , environmental health
Troglitazone (TGZ) causes delayed, life‐threatening drug‐induced liver injury in some patients but was not hepatotoxic in rats. This study investigated altered bile acid homeostasis as a mechanism of TGZ hepatotoxicity using a systems pharmacology model incorporating drug/metabolite disposition, bile acid physiology/pathophysiology, hepatocyte life cycle, and liver injury biomarkers. In the simulated human population, TGZ (200–600 mg/day × 6 months) resulted in delayed increases in serum alanine transaminase >3× the upper limit of normal in 0.3–5.1%, with concomitant bilirubin elevations >2× the upper limit of normal in 0.3–3.6%, of the population. By contrast, pioglitazone (15–45 mg/day × 6 months) did not elicit hepatotoxicity, consistent with clinical data. TGZ was not hepatotoxic in the simulated rat population. In summary, mechanistic modeling based only on bile acid effects accurately predicted the incidence, delayed presentation, and species differences in TGZ hepatotoxicity, in addition to predicting the relative liver safety of pioglitazone. Systems pharmacology models integrating physiology and experimental data can evaluate drug‐induced liver injury mechanisms and may be useful to predict the hepatotoxic potential of drug candidates. Clinical Pharmacology & Therapeutics (2014); 96 5, 589–598. doi: 10.1038/clpt.2014.158