薬理と治療

Abstract

Serious drug-induced liver injuries were reported in a uricosuric drug, benzbromarone. We investigated the risk of liver injury for dotinurad, a newly created uricosuric drug candidate, on hepatocellular injury, cholestasis, activation of apoptotic pathway, covalent binding, inhibition of mitochondrial function and stimulation of immune response in nonclinical studies. In 13-week, 26-week and 39-week oral dose toxicity studies of dotinurad in rats and monkeys, hepatocellular injury, cholestasis or apoptosis was not observed at the highest dose levels, and exposures at the highest dose levels were 264 to 781 times the clinical exposure. In an in vitro study, covalent binding of 14C-dotinurad to human hepatocytes was 13.8 pmol/mg protein and taking the maximum recommended human dose（4 mg）into consideration, dotinurad was classified in the Safe zone based on the zone classification system. In in vitro studies, dotinurad inhibited mitochondrial respiration using succinate and glutamate as substrates with the IC50 values of 30 and 23μmol/L, and these concentrations were 51 and 39 times the clinical exposure, respectively; however, dotinurad had little effect on mitochondrial enzyme complexesⅠ to Ⅳ at 100 μmol/L. In an in vitro study on stimulation of immune response, dotinurad increased IL-8 production from THP-1 cells at 30μmol/L, and this concentration was 51 times the clinical exposure. In conclusion, there was no finding suggestive of drug-induced liver injury by dotinurad through hepatocellular injury, cholestasis, activation of apoptotic pathway, covalent binding, inhibition of mitochondrial function and stimulation of immune response, taking into consideration the maximum recommended human dose and clinical exposure.