Shotaro Uehara: Liver Engineering Laboratory, Department of Applied Research for Laboratory Animals, Central Institute for Experimental Animals, Kawasaki 210-0821, Japan. Electronic address: s-uehara@ciea.or.jp.
Masahiko Yasuda: Pathology Center, Central Institute for Experimental Animals, Kawasaki 210-0821, Japan.
Yuichiro Higuchi: Liver Engineering Laboratory, Department of Applied Research for Laboratory Animals, Central Institute for Experimental Animals, Kawasaki 210-0821, Japan.
Nao Yoneda: Liver Engineering Laboratory, Department of Applied Research for Laboratory Animals, Central Institute for Experimental Animals, Kawasaki 210-0821, Japan.
Kenji Kawai: Pathology Center, Central Institute for Experimental Animals, Kawasaki 210-0821, Japan.
Masami Suzuki: Translational Research Division, Central Institute for Experimental Animals, Kawasaki 210-0821, Japan.
Hiroshi Yamazaki: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida 194-8543, Japan.
Hiroshi Suemizu: Liver Engineering Laboratory, Department of Applied Research for Laboratory Animals, Central Institute for Experimental Animals, Kawasaki 210-0821, Japan.
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 the 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 mice with humanized livers (humanized-liver mice). The 2-quinolinone-SGX523 formation activity was higher in humanized-liver mouse and human hepatocytes than in mouse hepatocytes. Additionally, this activity in the liver cytosolic fraction from humanized-liver mice was inhibited by the AOX inhibitors raloxifene and hydralazine. After oral SGX523 administration, higher maximum concentrations, larger areas under the plasma concentration versus time curves, and higher urinary concentrations of 2-quinolinone-SGX523 were observed in humanized-liver mice than in non-humanized mice. Serum creatinine and blood urea nitrogen levels were elevated in humanized-liver mice following repeated oral SGX523 administration. The accumulation of amorphous material in the tubules and infiltration of inflammatory cells around tubules were observed in the kidneys of humanized-liver mice after repeated oral SGX523 administration. These findings demonstrate that humanized-liver mice are useful for understanding the metabolism and toxicity of SGX523.
