RT Journal Article
SR Electronic
T1 Interactions between cyclophosphamide and doxorubicin metabolism in rats. II. Effect of cyclophosphamide on the aldoketoreductase system.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 271
OP 274
VO 237
IS 1
A1 P Dodion
A1 S R Akman
A1 J M Tamburini
A1 C E Riggs, Jr
A1 O M Colvin
A1 N R Bachur
YR 1986
UL http://jpet.aspetjournals.org/content/237/1/271.abstract
AB 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.