Factors affecting the toxicity and metabolism of OMPA (octamethylpyrophosphoramide) in rats.

Abstract

Octamethylpyrophosphoramide (OMPA) is a potent inhibitor of cholinesterase in vivo. However, OMPA itself is a very weak inhibitor, but it is converted to a potent inhibitor following oxidation by liver microsomes (1-4). In a pervious paper it is reported that the administration of thiopental or phenaglycodol markedly increased the toxicity of OMPA in female rats (5). Since the joint administration of ethionine with thiopental or phenaglycodol completely blocked the effect of thiopental or phenaglycodol, it was postulated that the induction of microsomal enzyme which activates the metabolism of OMPA was involved in the increased toxicity after thiopental or phenaglycodol treatment. In the present investigation, the effect of phenobarbital and methylcholanthrene on the toxicity and metabolism of OMPA in female and male rats were studied to confirm this postulation. Phenobarbital and methylcholanthrene are well known inducers of drug-metabolizing enzymes of liver microsomes (6-8). However, the administration of both drugs likely give different effects on the microsomal enzymes (9-11). The typical difference were also evidenced in the present works. In addition the marked sex difference was observed on the metabolism of many drugs by liver microsomes, and the metabolism of OMPA in male rats was much faster than that in female rats (2, 12-16). In the present studies the marked sex difference was also observed in the effect of phenobarbital and methylcholanthrene on the metabolism and toxictity of OMPA. These results may offer a typical example for the role of the metabolism of drugs by liver microsomes for the determination of drug toxicity.