Kehoe J E, Harvey L P, Daly J M
Cancer Res. 1986 Aug;46(8):4047-52.
Controversy exists as to whether administration of a chemically defined diet alters toxicity to chemotherapy. The purpose of this study was to evaluate toxicity to methotrexate in rats fed a chemically defined liquid diet or a regular chow diet. In the first study, 48 adult rats were randomized to be fed a chemically defined liquid diet or a regular diet for 14 days when methotrexate (25 or 50 mg/kg) was given. All liquid diet rats became anorexic and died within 96 h, while no deaths were observed in rats fed regular diet. When 20 liquid diet and regular diet rats were pair-fed to equalize caloric intake before and after methotrexate administration, similar mortality results occurred. In a second study, methotrexate (50 mg/kg) or saline was given and 60 h later all animals were sacrificed to obtain small bowel luminal cultures and tissue sections for histological evaluation. Administration of the liquid diet altered small bowel flora to predominantly Escherichia coli and Pseudomonas sp. and histology showed severe small bowel mucosal enteritis in comparison with regular diet rats. To evaluate whether the changes in intestinal flora or alterations in drug pharmacokinetics were responsible for the increased mortality, two additional studies were done. Gentamicin (4.8 mg/kg/day) was given p.o. or i.m. to the rats on the chemically defined liquid diet. A significant reduction of intraluminal bacteria occurred, but survival time was not improved in animals receiving antibiotics. When mean serum methotrexate levels were analyzed in non-antibiotic-treated rats, drug concentrations were significantly increased at 24, 36, and 48 h after methotrexate injection in the elemental liquid diet rats compared with chow diet rats. Administration of a chemically defined liquid diet to rats receiving methotrexate increased the occurrence and severity of intestinal enteritis, altered intraluminal bowel flora, and decreased clearance of methotrexate from the serum.
关于给予化学成分明确的饮食是否会改变化疗毒性存在争议。本研究的目的是评估喂食化学成分明确的液体饮食或常规饲料的大鼠对甲氨蝶呤的毒性。在第一项研究中，48只成年大鼠被随机分为两组，分别喂食化学成分明确的液体饮食或常规饮食14天，然后给予甲氨蝶呤（25或50mg/kg）。所有喂食液体饮食的大鼠均出现厌食并在96小时内死亡，而喂食常规饮食的大鼠未观察到死亡。当在给予甲氨蝶呤前后将20只喂食液体饮食和常规饮食的大鼠进行配对喂养以平衡热量摄入时，出现了类似的死亡率结果。在第二项研究中，给予甲氨蝶呤（50mg/kg）或生理盐水，60小时后处死所有动物，获取小肠腔培养物和组织切片进行组织学评估。与常规饮食的大鼠相比，给予液体饮食改变了小肠菌群，使其主要为大肠杆菌和假单胞菌属，并且组织学显示严重的小肠黏膜肠炎。为了评估肠道菌群的变化或药物药代动力学的改变是否是死亡率增加的原因，又进行了另外两项研究。对喂食化学成分明确的液体饮食的大鼠口服或肌肉注射庆大霉素（4.8mg/kg/天）。肠腔内细菌显著减少，但接受抗生素治疗的动物的存活时间并未改善。当对未接受抗生素治疗的大鼠的平均血清甲氨蝶呤水平进行分析时，与喂食普通饲料的大鼠相比，在给予甲氨蝶呤后24、36和48小时，食用元素液体饮食的大鼠的药物浓度显著升高。给接受甲氨蝶呤的大鼠喂食化学成分明确的液体饮食会增加肠炎的发生率和严重程度，改变肠腔内菌群，并降低血清中甲氨蝶呤的清除率。
