The evolution of strategies to minimise the risk of human drug-induced liver injury (DILI) in drug discovery and development.

Early identification of toxicity associated with new chemical entities (NCEs) is critical in preventing late-stage drug development attrition. Liver injury remains a leading cause of drug failures in clinical trials and post-approval withdrawals reflecting the poor translation between traditional preclinical animal models and human clinical outcomes. For this reason, preclinical strategies have evolved over recent years to incorporate more sophisticated human in vitro cell-based models with multi-parametric endpoints.

Metabolic Hydrolysis of Aromatic Amides in Selected Rat, Minipig, and Human In Vitro Systems.

The release of aromatic amines from drugs and other xenobiotics resulting from the hydrolysis of metabolically labile amide bonds presents a safety risk through several mechanisms, including geno-, hepato- and nephrotoxicity. Whilst multiple in vitro systems used for studying metabolic stability display serine hydrolase activity, responsible for the hydrolysis of amide bonds, they vary in their efficiency and selectivity. Using a range of amide-containing probe compounds (0.

A combined in vitro approach to improve the prediction of mitochondrial toxicants.

Drug induced mitochondrial dysfunction has been implicated in organ toxicity and the withdrawal of drugs or black box warnings limiting their use. The development of highly specific and sensitive in vitro assays in early drug development would assist in detecting compounds which affect mitochondrial function. Here we report the combination of two in vitro assays for the detection of drug induced mitochondrial toxicity.

Predicting in vivo phospholipidosis-inducing potential of drugs by a combined high content screening and in silico modelling approach.

Drug induced phospholipidosis (PLD) is an adverse side effect which can affect registration of new drug entities. Phospholipids can accumulate in lysosomes, organelles essential in cellular biogenesis and if compromised can lead to cellular toxicity. Drug accumulation in lysosomes (lysosomotropism) is a known mechanism leading to PLD, however phospholipidosis can also occur indirectly by altering synthesis and processing of phospholipids.