Identification of structure-activity relationships for adverse effects of pharmaceuticals in humans: Part C: use of QSAR and an expert system for the estimation of the mechanism of action of drug-induced hepatobiliary and urinary tract toxicities.

This report describes an in silico methodology to predict off-target pharmacologic activities and plausible mechanisms of action (MOAs) associated with serious and unexpected hepatobiliary and urinary tract adverse effects in human patients. The investigation used a database of 8,316,673 adverse event (AE) reports observed after drugs had been marketed and AEs noted in the published literature that were linked to 2124 chemical structures and 1851 approved clinical indications. The Integrity database of drug patent and literature studies was used to find pharmacologic targets and proposed clinical indications.

Identification of structure-activity relationships for adverse effects of pharmaceuticals in humans: Part B. Use of (Q)SAR systems for early detection of drug-induced hepatobiliary and urinary tract toxicities.

This report describes the development of quantitative structure-activity relationship (QSAR) models for predicting rare drug-induced liver and urinary tract injury in humans based upon a database of post-marketing adverse effects (AEs) linked to approximately 1600 chemical structures. The models are based upon estimated population exposure using AE proportional reporting ratios. Models were constructed for 5 types of liver injury (liver enzyme disorders, cytotoxic injury, cholestasis and jaundice, bile duct disorders, gall bladder disorders) and 6 types of urinary tract injury (acute renal disorders, nephropathies, bladder disorders, kidney function tests, blood in urine, urolithiases).