Tirmenstein Mark, Horvath Joseph, Graziano Michael, Mangipudy Raja, Dorr Thomas, Colman Karyn, Zinker Bradley, Kirby Mark, Cheng Peter T W, Patrone Laura, Kozlosky John, Reilly Timothy P, Wang Victor, Janovitz Evan
Bristol-Myers Squibb, Drug Safety Evaluation, New Brunswick, New Jersey, USA
Bristol-Myers Squibb, Drug Safety Evaluation, New Brunswick, New Jersey, USA.
Toxicol Pathol. 2015 Aug;43(6):825-37. doi: 10.1177/0192623315581020. Epub 2015 Jun 17.
Glucokinase (GK) catalyzes the initial step in glycolysis and is a key regulator of glucose homeostasis. Therefore, glucokinase activators (GKa) have potential benefit in treating type 2 diabetes. Administration of a Bristol-Myers Squibb GKa (BMS-820132) to healthy euglycemic Sprague-Dawley (SD) rats and beagle dogs in 1 mo toxicology studies resulted in marked and extended hypoglycemia with associated clinical signs of toxicity and degenerative histopathological changes in the stomach, sciatic nerve, myocardium, and skeletal muscles at exposures comparable to those expected at therapeutic clinical exposures. To investigate whether these adverse effects were secondary to exaggerated pharmacology (prolonged hypoglycemia), BMS-820132 was administered daily to male Zucker diabetic fatty (ZDF) rats for 1 mo. ZDF rats are markedly hyperglycemic and insulin resistant. BMS-820132 did not induce hypoglycemia, clinical signs of hypoglycemia, or any of the histopathologic adverse effects observed in the 1 mo toxicology studies at exposures that exceeded those observed in SD rats and dogs. This indicates that the toxicity observed in euglycemic animals was secondary to the exaggerated pharmacology of potent GK activation. This study indicates that ZDF rats, with conventional toxicity studies, are a useful disease model for testing antidiabetic agents and determining toxicities that are independent of prolonged hypoglycemia.
葡萄糖激酶（GK）催化糖酵解的第一步，是葡萄糖稳态的关键调节因子。因此，葡萄糖激酶激活剂（GKa）在治疗2型糖尿病方面具有潜在益处。在为期1个月的毒理学研究中，给健康的血糖正常的斯普拉格-道利（SD）大鼠和比格犬施用百时美施贵宝的GKa（BMS-820132），在与治疗性临床暴露预期相当的暴露水平下，导致明显且持续时间延长的低血糖，并伴有毒性相关的临床体征以及胃、坐骨神经、心肌和骨骼肌的退行性组织病理学变化。为了研究这些不良反应是否继发于过度药理学作用（长时间低血糖），将BMS-820132每日施用于雄性Zucker糖尿病脂肪（ZDF）大鼠，持续1个月。ZDF大鼠明显高血糖且胰岛素抵抗。在超过SD大鼠和犬类所观察到的暴露水平下，BMS-820132未诱导低血糖、低血糖的临床体征或在为期1个月的毒理学研究中观察到的任何组织病理学不良反应。这表明在血糖正常的动物中观察到的毒性继发于强效GK激活的过度药理学作用。这项研究表明，通过传统毒性研究，ZDF大鼠是用于测试抗糖尿病药物以及确定与长时间低血糖无关的毒性的有用疾病模型。
