title: Systems pharmacology modeling predicts delayed presentation and species differences in bile acid-mediated troglitazone hepatotoxicity.
abstract: 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.
authors: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors: K
authors: K
authors: Yang
authors: The Hamner-UNC Institute for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina, USA.
authors: J L
authors: JL
authors: Woodhead
authors: 1] Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA [2] The Hamner-UNC Institute for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina, USA.
authors: P B
authors: PB
authors: Watkins
authors: The Hamner-UNC Institute for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina, USA.
authors: B A
authors: BA
authors: Howell
authors: 1] Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA [2] Current address: UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors: K L R
authors: KL
authors: Brouwer
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001647:Bile Acids and Salts / Q000502:physiology*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D002839:Chromans / Q000633:toxicity*; D006801:Humans; D007004:Hypoglycemic Agents / Q000633:toxicity*; D008297:Male; D008954:Models, Biological; D051381:Rats; D012044:Regression Analysis; D013045:Species Specificity; D045162:Thiazolidinediones / Q000633:toxicity*; D000077288:Troglitazone
chemical_list: C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D002839:Chromans; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000410:Alanine Transaminase; D000077288:Troglitazone