7 research outputs found
Temperature-dependent development and reproduction of the boll weevil (Coleoptera: Curculionidae)
Migration and the effect of three environmental factors on the pre-reproductive period of the cotton-boliworm moth, Helicoverpa armigera
Traffic related PM2.5 air quality: Policy options for developing Pacific Island countries
Systems Pharmacology Modeling Predicts Delayed Presentation and Species Differences in Bile AcidâMediated Troglitazone Hepatotoxicity
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 (200â600mg/dayĂ6months) resulted in delayed increases in serum ALT>3Ă ULN in 0.3â5.1% of the population with concomitant bilirubin elevations>2Ă ULN in 0.3â3.6%. In contrast, pioglitazone (15â45mg/dayĂ6months) 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