SGX523 causes renal toxicity through aldehyde oxidase-mediated less-soluble metabolite formation in chimeric NOG-TKm30 mice with humanized livers
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- UEHARA Shotaro
- Central Institute for Experimental Animals
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- YASUDA Masahiko
- Central Institute for Experimental Animals
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- HIGUCHI Yuichiro
- Central Institute for Experimental Animals
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- YONEDA Nao
- Central Institute for Experimental Animals
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- KAWAI Kenji
- Central Institute for Experimental Animals
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- YAMAZAKI Hiroshi
- Showa Pharmaceutical University
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- SUEMIZU Hiroshi
- Central Institute for Experimental Animals
Bibliographic Information
- Other Title
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- SGX523はヒト肝キメラマウスにおいてアルデヒド酸化酵素による難溶性代謝物形成を介して腎毒性を引き起こす
Abstract
<p>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.</p>
Journal
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- Annual Meeting of the Japanese Society of Toxicology
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Annual Meeting of the Japanese Society of Toxicology 50.1 (0), P3-287-, 2023
The Japanese Society of Toxicology
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Details 詳細情報について
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- CRID
- 1390299395584778368
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- Text Lang
- ja
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- Data Source
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- JaLC
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- Abstract License Flag
- Disallowed