Johnson & Johnson Pharmaceutical Research & Development LLC, Raritan, NJ 08869, USA.
J Appl Toxicol. 2011 May;31(4):342-54. doi: 10.1002/jat.1592. Epub 2010 Nov 18.
Unscheduled mortality preceded by adverse respiratory clinical signs in rats dosed by oral gavage may not only be caused by technical gavage error or systemic toxicity but may also be caused by gastro-esophageal reflux and subsequent aspiration of high concentrations of drug formulation. In a 3 week oral gavage rat toxicity study for an early drug development compound, preterminal deaths (approximately 20% of animals) at high doses (≥1000 mg kg(-1) ) and concentrations (≥60 mg ml(-1) ) were preceded by recurrent dyspnea, rales or excessive salivation, without evidence of accidental intrapulmonary gavage error. Histological evaluation revealed extensive necrosis and inflammatory changes in the upper respiratory tract, especially in the nasal turbinates and/or nasopharynx. The presence of food particles in inflammatory exudates suggested a retrograde aspiration of stomach content with test formulation via the nasopharyngeal duct into the posterior region of the nose. In contrast, no mortality or adverse respiratory effects were observed in rats following 2 week intravenous administration at comparable exposures or oral gavage administration at lower concentrations (≤20 mg ml(-1) ). In a pharmacology study, the compound caused a dose-dependent increase in gastric content (partly due to inhibition of gastric emptying), providing a pharmacological basis for the suspected gavage-mediated gastroesophageal reflux. Reducing the dose volume and dosing fasted animals substantially reduced or eliminated the respiratory effects and mortality at the high test article concentrations, demonstrating that the adverse effects are related to the gavage method.
经口服灌胃给予药物的大鼠出现未计划的死亡，并伴有呼吸临床症状恶化，这不仅可能是由于技术灌胃错误或全身毒性引起的，还可能是由于胃食管反流和随后吸入高浓度药物制剂引起的。在一项用于早期药物开发化合物的 3 周口服灌胃大鼠毒性研究中，高剂量（≥1000mg/kg）和高浓度（≥60mg/ml）组的大鼠在预终末期（约 20%的动物）死亡之前，出现反复呼吸困难、啰音或过度流涎，但没有证据表明发生了意外的肺内灌胃错误。组织学评估显示，上呼吸道（尤其是鼻甲和/或鼻咽部）广泛发生坏死和炎症变化。炎症渗出物中存在食物颗粒提示胃内容物通过鼻咽管逆行吸入至鼻后部，与试验制剂一起发生。相比之下，在以类似暴露量进行的 2 周静脉内给药或以较低浓度（≤20mg/ml）进行的口服灌胃给药后，大鼠没有死亡或出现呼吸不良反应。在一项药理学研究中，该化合物引起胃内容物剂量依赖性增加（部分原因是胃排空抑制），为怀疑的灌胃介导的胃食管反流提供了药理学依据。减少剂量体积和给禁食动物灌胃可显著减少或消除高测试物质浓度下的呼吸作用和死亡率，表明这些不良反应与灌胃方法有关。
