title: Interactions between cyclophosphamide and doxorubicin metabolism in rats. II. Effect of cyclophosphamide on the aldoketoreductase system.
abstract: Under anaerobic conditions, in comparison to liver microsomes obtained from normal controls, liver microsomes obtained from rats pretreated with cyclophosphamide formed significantly less 7-deoxydoxorubicinol aglycone (P less than or equal to .05), whereas the disappearance of doxorubicin and the formation of 7-deoxydoxorubicin aglycone were unaffected. When directly investigated, the reduction of 7-deoxydoxorubicin aglycone to 7-deoxydoxorubicinol aglycone by microsomes was inhibited by cyclophosphamide pretreatment. Liver cytosols from controls and cyclophosphamide-treated rats reduced daunorubicin to daunorubicinol and 7-deoxydoxorubicin aglycone to 7-deoxydoxorubicinol aglycone at the same rate, which indicates the lack of effect of cyclophosphamide pretreatment on the cytosolic aldoketoreductase. The results suggest the existence of a microsomal carbonyl reduction system for anthracycline antibiotics and indicate that cyclophosphamide does affect the metabolism of doxorubicin; in rats, this interaction results only in an alteration of the relative concentrations of presumably inactive metabolites, the 7-deoxyaglycones. The importance of these findings for the pharmacological interaction between doxorubicin and cyclophosphamide in humans remains to be investigated.
mesh_terms: D000429:Alcohol Oxidoreductases / Q000378:metabolism*; D000818:Animals; D003520:Cyclophosphamide / Q000378:metabolism* / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000378:metabolism*; D004347:Drug Interactions; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats
chemical_list: D004317:Doxorubicin; D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System; D000429:Alcohol Oxidoreductases