SGX523 causes renal toxicity through aldehyde oxidase-mediated less-soluble metabolite formation in chimeric NOG-TKm30 mice with humanized livers

Abstract

SGX523 is a c-Met tyrosine kinase inhibitor that failed in clinical trials because of renal toxicity caused by crystal deposits in renal tubules. SGX523 is metabolized by aldehyde oxidase (AOX) in a species-dependent manner to a considerably less-soluble 2-quinolinone SGX523, which is likely involved in the clinically observed obstructive nephropathy. This study investigated the metabolism and renal toxicity of SGX523 in chimeric NOG-TKm30 mice with humanized liver (humanized-liver mice). The 2-quinolinone SGX523 formation activity was higher in hepatocytes from humanized-liver mice and humans than in mouse hepatocytes. Additionally, this activity in the liver cytosolic fraction from humanized-liver mice was inhibited by raloxifene and hydralazine, also known as human AOX inhibitors. Higher maximum concentrations, areas under the plasma concentration versus time curves, and urinary concentrations of 2-quinolinone SGX523 were observed in humanized-liver mice more than in nonhumanized mice after oral SGX523 administration. The blood urea nitrogen and serum creatinine levels were elevated in humanized-liver mice due to the repeated oral SGX523 administration. The accumulation of granular material in the tubules and infiltration of inflammatory cells around the proximal tubules were observed in the kidneys of humanized-liver mice after repeated oral SGX523 administration. Therefore, humanized-liver mice are an important animal model for understanding the metabolism and toxicity of SGX523.