Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas 72079, USA.
Toxicol Sci. 2012 Apr;126(2):317-24. doi: 10.1093/toxsci/kfr348. Epub 2012 Jan 6.
The intentional adulteration of pet food with melamine and cyanuric acid has been implicated in the kidney failure and death of a large number of cats and dogs in the United States. Although individually these compounds present low toxicity in a range of experimental animals, coexposure can lead to the formation of melamine cyanurate crystals in the nephrons and eventual kidney failure. Given this mode of action, a good understanding of the pharmacokinetic profiles of melamine and cyanuric acid and their combinations is essential to define properly the risk associated with different exposure scenarios. Previous studies have investigated the individual pharmacokinetic profiles of melamine and cyanuric acid. In this work, we report a comparison between the pharmacokinetic profiles of melamine and cyanuric acid administered individually, administered simultaneously as the individual compounds, and administered as a preformed melamine cyanurate complex. Although the oral coadministration of 1 mg/kg body weight of melamine and cyanuric acid did not alter significantly the pharmacokinetic profiles in relation to those determined upon individual oral administration of each compound, the administration of equal amounts of each triazine as the preformed melamine cyanurate complex significantly altered the pharmacokinetics, with reduced bioavailability of both compounds, lower observed maximum serum concentrations, delayed peak concentrations, and prolonged elimination half lives. These results indicate that in order to estimate properly the combined nephrotoxic potential of melamine and cyanuric acid, the experimental design of toxicological experiments and the evaluation of animal or human exposure scenarios should consider the detailed mode of exposure, with particular emphasis on any possible ex vivo formation of melamine cyanurate.
三聚氰胺和三聚氰酸蓄意掺入宠物食品，导致美国大量猫和狗的肾衰竭和死亡。尽管这些化合物在一系列实验动物中单独表现出低毒性，但共同暴露会导致肾单位中三聚氰胺三聚氰酸盐晶体的形成，并最终导致肾衰竭。鉴于这种作用模式，深入了解三聚氰胺和三聚氰酸及其组合的药代动力学特征对于正确定义不同暴露场景相关的风险至关重要。先前的研究已经调查了三聚氰胺和三聚氰酸的个体药代动力学特征。在这项工作中，我们报告了单独给予、同时给予作为单个化合物以及预先形成的三聚氰胺三聚氰酸盐复合物给予时，三聚氰胺和三聚氰酸药代动力学特征的比较。尽管以 1mg/kg 体重的剂量同时给予 1mg/kg 体重的三聚氰胺和三聚氰酸不会显著改变与单独给予每种化合物时确定的药代动力学特征，但以预先形成的三聚氰胺三聚氰酸盐复合物给予等量的每种三嗪会显著改变药代动力学特征，导致两种化合物的生物利用度降低、观察到的最大血清浓度降低、峰值浓度延迟和消除半衰期延长。这些结果表明，为了正确估计三聚氰胺和三聚氰酸的联合肾毒性潜力，毒理学实验的实验设计和动物或人类暴露场景的评估应考虑到详细的暴露方式，特别强调任何可能的三聚氰胺三聚氰酸盐体外形成。
