Geary R S, Swynnerton N F, Timmons S F, Mangold D J
Southwest Research Institute, San Antonio, Texas 78228-0510.
Biopharm Drug Dispos. 1991 May;12(4):275-84. doi: 10.1002/bdd.2510120405.
A circulating in situ rat small intestine absorption model was used to study the lumenal metabolism and absorption of [14C]WR-1065. WR-1065 was found to be more tissue reactive and toxic than its phosphorylated form, ethiofos, at equimolar perfusate concentrations. The disappearance profiles of the radiolabeled drug and free WR-1065 indicate that WR-1065 is extensively metabolized in the intestinal lumen prior to absorption. Coadministration of disodium ethylenediaminetetraacetic acid enhances the absorption of the free thiol although not to the same extent as seen with ethiofos. Perfusion of WR-1065 in citrate buffer decreased lumenal degradation of the drug but resulted in decreased absorption. The total material converted to WR-1065 portal blood profiles following ethiofos and WR-1065 perfusion were altered possibly due to distribution and metabolism differences. This study coupled with earlier work completed on ethiofos have increased our understanding of the significant barriers to absorption observed following oral administration of these compounds.
采用循环原位大鼠小肠吸收模型研究了[14C]WR-1065的肠腔代谢及吸收情况。研究发现，在等摩尔灌注液浓度下，WR-1065比其磷酸化形式乙硫磷具有更高的组织反应性和毒性。放射性标记药物和游离WR-1065的消失曲线表明，WR-1065在吸收前在肠腔中被广泛代谢。乙二胺四乙酸二钠的共同给药可增强游离硫醇的吸收，尽管程度不如乙硫磷。在柠檬酸盐缓冲液中灌注WR-1065可减少药物的肠腔降解，但导致吸收减少。乙硫磷和WR-1065灌注后转化为WR-1065门静脉血曲线的总物质可能由于分布和代谢差异而发生改变。这项研究以及早期对乙硫磷完成的工作，加深了我们对口服这些化合物后观察到的显著吸收障碍的理解。
