FACTORS AFFECTING THE DELAYED NEUROTOXICITY OF LEPTOPHOS ANALOGS (PHARMACOKINETICS, ORGANOPHOSPHORUS, NTE, INTRAVENOUS)

Leptophos (L), desbromoleptophos (DBL) and ethyl leptophos (EL) are equipotent against the proposed target receptor, Neuropathy Target Esterase (NTE) towards initiation of Organophosphorus-Induced Delayed Neuropathy (OPIDN), but neuropathic potential following oral administration of the compounds in hens are on the order of 10:1:500, respectively. Possible reasons underlying the anomaly were sought. Analysis of NTE inhibition with respect to time did not reveal a substantial lag between spinal cord and brain NTE for any of the compounds, but activity in both brain and spinal cord following EL administration recovered more rapidly than after L. A comparison of iv and oral potencies of the analogs indicated that L and DBL were equipotent towards induction of neuropathy by the iv route. EL is still 4X less neurotoxic by this route. Radiolabel studies on L and DBL indicated that the two are identical with respect to distribution from the central compartment, elimination and metabolism. Radioactivity was excreted primarily into the urine as water-soluble metabolites. Distribution from the central compartment was at least tri-exponential. Incomplete absorption following oral administration appears to limit the delayed neurotoxicity of L. Factors other than incomplete absorption must contribute to the attenuated neurotoxic potential of EL.