Keenan K P, Laroque P, Soper K A, Morrissey R E, Dixit R
Merck Research Laboratories, West Point, PA 19486, USA.
Exp Toxicol Pathol. 1996 Feb;48(2-3):139-44. doi: 10.1016/S0940-2993(96)80034-0.
Ad libitum (AL) overfeeding is the most significant uncontrolled variable effecting the rodent bioassay. There is a highly significant correlation between food consumption, the resultant body weight, and two-year survival in laboratory rats. We have studied the effects of AL overfeeding, moderate dietary restriction (DR) and several modified diets on Sprague-Dawley (SD) rat longevity, spontaneous disease, carcinogenesis and the toxicity of pharmaceuticals. AL feeding of diets varying in protein, fiber and metabolizable energy content did not significantly alter two-year rat survival. Moderate DR (within the range of reported AL food intake) of all diets tested significantly improved survival and delayed the onset of spontaneous degenerative disease and diet-related tumors compared to AL-fed rats. Moderate DR resulted in a similar incidence of spontaneous tumors by 2 years, however, the tumors were more likely to be incidental and not result in early mortality. There was a decreased, age-adjusted incidence of pituitary and mammary gland tumors, but tumor volume and growth time was similar between AL and DR groups indicating similar tumor progression with a delay in tumor onset. Moderate DR did not change Phase I and Phase II drug metabolizing enzyme levels and did not significantly alter the toxicological response to 5 pharmaceuticals tested at maximum tolerated doses (MTDs). Additional studies with 4 pharmaceutical candidates did demonstrate that moderate DR allowed higher doses of compounds to be given before classical MTDs were observed. However, toxicokinetic studies of two of these compounds demonstrated steady state systemic exposures that were either equal of higher in the moderate DR fed rats. These and other data indicate that the moderate DR fed SD rat is a more appropriately controlled rodent model for toxicity and carcinogenicity studies to assess human safety of candidate pharmaceuticals.
随意（AL）过量喂食是影响啮齿动物生物测定的最显著的未控制变量。在实验室大鼠中，食物摄入量、由此产生的体重和两年生存率之间存在高度显著的相关性。我们研究了随意过量喂食、适度饮食限制（DR）和几种改良饮食对斯普拉格-道利（SD）大鼠寿命、自发性疾病、致癌作用和药物毒性的影响。喂食蛋白质、纤维和可代谢能量含量不同的饮食，对大鼠两年生存率没有显著影响。与随意喂食的大鼠相比，对所有测试饮食进行适度饮食限制（在报道的随意食物摄入量范围内）可显著提高生存率，并延迟自发性退行性疾病和与饮食相关肿瘤的发生。到2年时，适度饮食限制导致的自发性肿瘤发生率相似，然而，这些肿瘤更可能是偶然发生的，不会导致早期死亡。垂体和乳腺肿瘤的年龄调整发病率有所降低，但随意喂食组和饮食限制组之间的肿瘤体积和生长时间相似，表明肿瘤进展相似，但肿瘤发生延迟。适度饮食限制不会改变I期和II期药物代谢酶水平，也不会显著改变在最大耐受剂量（MTDs）下测试的5种药物的毒理学反应。对4种候选药物的进一步研究确实表明，适度饮食限制允许在观察到经典最大耐受剂量之前给予更高剂量的化合物。然而，对其中两种化合物的毒代动力学研究表明，适度饮食限制喂养的大鼠的稳态全身暴露量要么相等，要么更高。这些以及其他数据表明，适度饮食限制喂养的SD大鼠是用于毒性和致癌性研究以评估候选药物对人类安全性的更合适的对照啮齿动物模型。
