Characterization of ethiofos absorption in the rat small intestine

Abstract

The absorption characteristics of ethiofos were studied using the rat in situ intestine circulating perfusion technique. Slow absorption kinetics were observed for ethiofos with varying rates of absorption and metabolism/degradation in situ as a function of buffer and absorption enhancers. In most cases less than 10 per cent of the radiolabeled compound is lost from the circulating perfusate in 90 min. In addition, over the same time period greater than 40 per cent of the intact parent compound was lost by degradation. Much of the difference can be accounted for in the formation of the free thiol metabolite. WR-1065, suggesting ester hydrolysis or metabolic activity. Good stability was observed in all perfusate systems ex vivo indicating that the degradation occurs in situ. The disodium salt of ethylenediaminetetraacetic acid (EDTA) was shown to be an effective absorption enhancer of ethiofos. The enhancement of intestinal absorption by EDTA was dose-dependent resulting in a 20-fold increase in blood levels of ethiofos in the portal blood. Follow-up studies in the rhesus monkey confirm this observation. Salicylate and dimethylsulfoxide (DMSO) also resulted in absorption enhancement although to a lesser degree than that seen after EDTA treatment. Addition of several alkaline phosphatase inhibitors did not significantly improve absorption of ethiofos in the rat small intestine. Proposed mechanism(s) for intestinal absorption and absorption enhancement of ethiofos are discussed.

Characterization of WR‐1065 absorption in the rat small intestine

“…the symmetrical disulfide of WR-1065 or mixed disulfides of the latter and endogenous sulfhydryl compounds such as cysteamine, glutathione and proteins). In the small intestine of the rat, ethiofos is metabolized to form WR-1065 and other unidentified metabolites prior to absorption (as reported in a paper submitted by R. S. Geary et al 16). Describing the absorption and lumenal metabolism of WR-1065 is important to understanding the poor bioavailability of ethiofos following oral administration.…”