In Vitro Metabolite Formation in Human Hepatocytes and Cardiomyocytes and Metabolism and Tissue Distribution in Monkeys of the 2'-C-Methylguanosine Prodrug BMS-986094 : Potential Role in Clinical Cardiovascular Toxicity.

BMS-986094, a 2'-C-methylguanosine prodrug for the treatment of chronic hepatitis C virus infection, was withdrawn from phase 2 clinical trials because of unexpected cardiac and renal toxicities. To better understand these toxicities, the in vitro metabolism of BMS-986094 in human hepatocytes (HHs) and human cardiomyocytes (HCMs) and the measurement of BMS-986094 and selected metabolites in monkey plasma and tissues were assessed. BMS-986094 was extensively metabolized by HHs and HCMs, resulting in more efficient formation and accumulation of the active triphosphorylated metabolite, INX-09114, and less efficient efflux of metabolites in HCMs.

Accurate prediction of drug-induced liver injury using stem cell-derived populations.

Despite major progress in the knowledge and management of human liver injury, there are millions of people suffering from chronic liver disease. Currently, the only cure for end-stage liver disease is orthotopic liver transplantation; however, this approach is severely limited by organ donation. Alternative approaches to restoring liver function have therefore been pursued, including the use of somatic and stem cell populations.

Thermal sensitisation by lonidamine of human melanoma cells grown at low extracellular pH.

Purpose: This study tested the ability of lonidamine (LND), a clinically applicable inhibitor of monocarboxylate transporters (MCT), to thermally sensitise human melanoma cells cultured at a tumour-like extracellular pH (pHe) 6.7.

Materials And Methods: Human melanoma DB-1 cells cultured at pHe 6.

Developing high-fidelity hepatotoxicity models from pluripotent stem cells.

Faithfully recapitulating human physiology "in a dish" from a renewable source remains a holy grail for medicine and pharma. Many procedures have been described that, to a limited extent, exhibit human tissue-specific function in vitro. In particular, incomplete cellular differentiation and/or the loss of cell phenotype postdifferentiation play a major part in this void.

Intracellular acidification abrogates the heat shock response and compromises survival of human melanoma cells.

This study tests the hypothesis that lowering intracellular pH (pHi) in melanoma cells grown at low extracellular pH (pHe) selectively abrogates 42 degrees C-induced heat shock protein (HSP) expression and reduces survival. Cells were acidified by a combination of a 0.2-pH-unit decrease in pHe coupled with the lactate/H+ transport inhibitor alpha-cyano-4-hydroxy-cinnamic acid (CNCn).