METABOLISM OF HEXAMETHYLPHOSPHORAMIDE AND RELATED COMPOUNDS

The metabolism of hexamethylphosphoramide (HMPA) has been studied in the rat and mouse. Three urinary metabolites were isolated from both species and identified as pentamethylphosphoramide (PMPA), N′,N′,N′',N‴''-tetramethylphosphoramide and N′,N′',N‴''-trimethylphosphoramide. Hexamethylthiophosphoramide (thio-HMPA), besides producing HMPA, is degraded by an alternative pathway to PMPA via pentamethylthiophosphoramide (thio-PMPA). Distribution studies with 32PHMPA indicated no specific localisation of labelled material in the tissues of either species. Metabolism of the homologues hexa-ethylphosphoramide (HEPA) and hexa-n-propylphosphoramide (HPPA) to N′,N′',N‴''-tri-ethylphosphoramide and N′,N″,N‴''-tri-n-propylphosphoramide respectively suggests general detoxification of such com- pounds by a stepwise series of dealkylations. Degradation of the phosphoramides by rat liver slices in vitro indicates that their metabolism occurs by a process of oxidative dealkylation. © 1968.