Cook Thomas J, Shenoy Smriti S
Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ 08854, USA.
Toxicology. 2003 Mar 3;184(2-3):125-33. doi: 10.1016/s0300-483x(02)00555-3.
The intestinal transport of chlorpyrifos (CPF), an organothiophosphate pesticide, was investigated using the single-pass intestinal perfusion (SPIP) technique in male, Sprague-Dawley rats. SPIP was performed in each isolated region of the small intestine (i.e. duodenum, jejunum and ileum) with three concentrations of CPF (0.1, 2.0 and 10 microM) at a flow rate of 0.25 ml/min. Preliminary binding and stability studies were conducted to ensure that the loss of CPF in the SPIP study can be attributed to intestinal absorption. The effective permeability (P(eff)) of CPF was determined for each segment and concentration. CPF exhibits a high intestinal permeability over the length of the small intestine indicative of compounds that are well absorbed. Decreases in permeability values at the highest CPF concentration studied in the duodenum and ileum suggest a saturable transport process. Based on these results, passive, transcellular diffusion dominates the intestinal transport mechanism of CPF, with a saturable transport process evident in the duodenum and ileum. The P(eff) of CPF is in the range of drugs with high intestinal permeability and high fraction of dose absorbed indicating that CPF readily crosses the intestine. The dependence of CPF's P(eff) on concentration in the duodenum and ileum suggests that CPF is transported by a combination of mechanisms across the intestine. Using established relationships, the human fraction dose absorbed for CPF was estimated to be >99%. The permeability values obtained from this study may be useful in models of exposure assessment.
采用单通道肠道灌注（SPIP）技术，在雄性Sprague-Dawley大鼠中研究了有机硫代磷酸酯农药毒死蜱（CPF）的肠道转运情况。在小肠的每个分离区域（即十二指肠、空肠和回肠）进行SPIP实验，使用三种浓度的CPF（0.1、2.0和10微摩尔），流速为0.25毫升/分钟。进行了初步的结合和稳定性研究，以确保SPIP研究中毒死蜱的损失可归因于肠道吸收。测定了每个肠段和浓度下毒死蜱的有效渗透率（P(eff)）。毒死蜱在小肠全长范围内表现出较高的肠道渗透率，表明该化合物易于吸收。在十二指肠和回肠中研究的最高毒死蜱浓度下，渗透率值降低，表明存在可饱和的转运过程。基于这些结果，被动的跨细胞扩散主导了毒死蜱的肠道转运机制，在十二指肠和回肠中可明显看到可饱和的转运过程。毒死蜱的P(eff)处于肠道渗透率高且吸收剂量分数高的药物范围内，表明毒死蜱易于穿过肠道。毒死蜱的P(eff)对十二指肠和回肠中浓度的依赖性表明，毒死蜱通过多种机制组合穿过肠道。利用既定关系，估计毒死蜱在人体中的吸收剂量分数>99%。本研究获得的渗透率值可能在暴露评估模型中有用。
