MAMMALIAN CONVERSION OF OCTAMETHYI,PYItOI’IIOS- PHORAMIDE TO A TOXIC PHOSPHORAMIDE N-OXIDE*

The interest in octamethylpyrophosphoramide (schradan) as a systemic insecticide (l-3) and in the treatment of myasthenia gravis (4) emphasizes the need for a better understanding of its mode of toxic action. Exposure of mammals to schradan leads to death, with the typical symptoms of acetylcholine poisoning after a definite lag period (5, 6). Yet schradan is only about one-millionth as effective a cholinesterase inhibitor in vitro as other anticholinesterase drugs with similar toxicity to mammals (7). This suggested a metabolism in tivo which was supported by the finding of an anticholinesterase in the blood of treated rabbits (7). Conversion of schradan by rat and rabbit liver slices in vitro to a cholinesterasc inhibitor has been demonstrated by several workers (5-S). Technical schradan preparations contain various components which have been studied in detail (9), including a weak anticholinesterase agent which is rapidly destroyed by incubation with liver homogenates, but this material is not the same as the liver slice metabolite (8). The conversion of schradan in viva appears to occur only in the liver (5, 10, 11). An oxidative conversion has been suggested for this reaction in view of the high oxygen tension necessary for efficient production of the act,& metabolite by liver slices (5). Gardiner and Kilby (7) consider the metabolism of schradan to yield a reactive phosphorylating, anticholinesterasc agent, possibly through the “fission of the P-O bond and the replacement of the -0-P(NMe& portion by some group X such that the P-X bond