was evaluated in female Sprague-Dawley rats. Erythrocyte acetylcholinesterase (AChE) ac-tivity was maximally inhibited 1 min after iv administration (38, 23, and 15 % of pretrcatment activity after 86, 250, and 690 Mg/kg, respectively) and recovered by 4 hr. Maximum AChE inhibition (63 % of pretreatment activity) was measured 45 min after oral dosing (690 jtg/kg) and activity recovered after 5 hr. Signs included urination, defecation, facial muscle fasciculations, salivation, and tremors. Carbosulfan was less toxic when given orally. Metabolic activation of carbosulfan to carbofuran (2,3-dihydro-2,2-dimethyl-7-benzofuranol methylcarbamate) was in-vestigated by measuring plasma concentrations 4, 30, and 240 min after iv (80-120 or 620-640 jig/kg) and oral (540-700 or 2030-2190 jig/kg) dosages of [carbonyl-14C]carbosulfan. Peak plasma concentrations were measured at 4 and 30 min after iv and oral exposure, respectively. Carbosulfan was rapidly activated to carbofuran. Reduction in AChE activity was better correlated (r = 0.97) with plasma concentration of [carbosulfan + carbofuran] and plasma carbofuran (r = 0.96) than with plasma carbosulfan (r = 0.73). Signs generally occurred when AChE activity was less than 65 % of pretreatment levels, corresponding to 40 pmol/ml [carbosulfan + carbofuran] in plasma. Based on regression analysis and metabolic studies, both carbosulfan and carbofuran contributed to the observed AChE inhibition; however, carbofuran, a more potent in vitro inhibitor and the usual predominant inhibitor in plasma, was responsible for most of the erythroevte AChE inhibition
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