Abstract

While investigating the physiologic disposition of cyclophosphamide, an alkylating agent, we observed that the drug produces a diuresis in rats and dogs. This investigation was undertaken to establish the nature of the diuresis and to elucidate the mechanism of action of the drug. Nor-nitrogen mustard, a metabolite of cyclophosphamide, also produced a diuretic response. Cyclophosphamide was ineffective in the absence of antidiuretic hormone (ADH), and it appeared that inhibition of the actions of ADH was responsible for the diuresis. Rats were pretreated with cyclophosphamide or nor-nitrogen mustard 2 hr before the administration of a water load and ADH. A partial inhibition of the ADH effect was observed. Drug-treated animals showed a partial inhibition of the effects of ADH released centrally by the administration of nicotine. Administration of solutions of cyclophosphamide or nor-nitrogen mustard incubated with ADH in vitro to water-loaded rats resulted in an antidiuretic effect. The hypotheses concerning the biochemical effects of ADH involve intermediates which possess potential sites for alkylation. Thus, the alkylating agents cyclophosphamide or nor-nitrogen mustard could indirectly inhibit the effects of ADH. While it appears that these alkylating agents inhibit the effects of ADH peripherally, a concomitant inhibition of ADH release or synthesis has not been ruled out.