title: The use of deuterated analogs in qualitative and quantitative investigations of the metabolism of cyclophosphamide (NSC-26271).
abstract: Ring-deuterated analogs of cyclophosphamide (CP) (4-d2, 5-d, 4,6-d4, and 4,5,6-d6 derivatives) have been used to study the influence of deuterium substitution on the rates of metabolic pathways involving oxidation at C-4, and on the rate of elimination of acrolein from aldophosphamide. The magnitude of the deuterium isotope effect (kH/kD) associated with appropriate C-deuteration has been related to antitumor activity against the ADJ/PC6 murine plasma cell tumor. Isotope effects of 2.2 and 1.8 respectively, for the formation of 4-ketocyclophosphamide (4-keto-CP) and carboxyphosphamide, caused little or no change in antitumor activity (4-d2 and 4,6-d4 analogs compared with CP), but an isotope effect of about 5.3 for the beta-elimination pathway, consequent on 5,5-dideuteration, was paralleled by a marked drop in potency (7-13-fold increase in ED90) of 5,5-dideuterated analogs compared with that of CP. Analogs tetradeuterated in the bis(2-chloroethyl)amino function were used to quantitate CP and 4-keto-CP in human plasma and urine using stable-isotope dilution and direct-insertion electron impact mass spectrometry. The negative optical rotation of CP recovered from human urine after administration of the racemlc drug gave evidence for stereoselectivity in the metabolism.
mesh_terms: D000171:Acrolein / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism*; D003903:Deuterium; D005260:Female; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000378:metabolism; D009374:Neoplasms, Experimental; D009588:Nitrogen Mustard Compounds / Q000378:metabolism; D011854:Radiochemistry; D051381:Rats; D013237:Stereoisomerism
chemical_list: D000970:Antineoplastic Agents; D009588:Nitrogen Mustard Compounds; D000171:Acrolein; D003520:Cyclophosphamide; D003903:Deuterium