Species-specific metabolism of SGX523 by aldehyde oxidase and the toxicological implications.
An investigation was conducted to follow up on the apparent species-dependent toxicity reported for 6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylthio)quinoline (SGX523), a mesenchymal-epithelial transition factor (c-MET) inhibitor that entered clinical development for the treatment of solid tumors. Patients treated with SGX523 exhibited compromised renal function presumably resulting from crystal deposits in renal tubules. Our independent metabo'lite profiling of SGX523 indicates that a major NADPH-independent, late-eluting metabolite [6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylthio)quinolin-2(1H)-one (M11)] was generated by monkey and human liver S-9, and to a lesser extent by rat S-9, whereas M11 was absent in dog S-9 incubations. We confirmed the identity of M11 as 2-quinolinone-SGX523. Experiments with various molybdenum hydroxylase inhibitors showed that aldehyde oxidase (AO), and not xanthine oxidase, metabolized SGX523 to M11 in monkey and human liver cytosol. In addition, the oxygen incorporated into M11 was derived from water rather than atmospheric oxygen, corroborating M11 formation via AO. After oral dosing in monkeys, metabolite profiling of plasma and urine showed that SGX523 was indeed metabolized to M11 and its N-demethyl analog (M8). In urine, M11 levels were approximately 70-fold greater than that of SGX523, and the solubility of M11 in urine was only 3% of that of SGX523. In summary, SGX523 is metabolized by AO in a species-specific manner to a markedly less-soluble metabolite, M11. We propose that M11 is likely involved in the observed obstructive nephropathy reported in clinical studies. Moreover, this study illustrates the need to conduct thorough metabolic evaluations early in drug development to select the most relevant nonclinical species for toxicological evaluation.
Diamond
Sharon
S
Incyte Corporation, Wilmington, Delaware 19880, USA. sdiamond@incyte.com
Boer
Jason
J
Maduskuie
Thomas P
TP
Falahatpisheh
Nikoo
N
Li
Yu
Y
Yeleswaram
Swamy
S
D042931:Aldehyde Oxidase / Q000378:metabolism*; D000818:Animals; D003600:Cytosol / Q000378:metabolism; D004285:Dogs; D006801:Humans; D008099:Liver / Q000378:metabolism; D008252:Macaca fascicularis; D008862:Microsomes, Liver / Q000378:metabolism; D010100:Oxygen; D011724:Pyridazines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D014230:Triazoles / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity
C547925:6-(6-(1-methyl-1H-pyrazol-4-yl)-(1,2,4)triazolo(4,3-b)pyridazin-3-ylsulfanyl)quinoline; D011724:Pyridazines; D014230:Triazoles; D042931:Aldehyde Oxidase; D010100:Oxygen