Activation of the anti-cancer drug ifosphamide by rat liver microsomal P450 enzymes

Biochem Pharmacol. 1993 Apr 22;45(8):1685-94. doi: 10.1016/0006-2952(93)90310-s.


The NADPH-dependent metabolism of ifosphamide catalyzed by rat liver microsomes was investigated in order to identify individual P450 enzymes that activate this anti-cancer drug and to ascertain their relationship to the P450 enzymes that activate the isomeric drug cyclophosphamide. Pretreatment of rats with phenobarbital or clofibrate increased by up to 8-fold the activation of both ifosphamide and cyclophosphamide catalyzed by isolated liver microsomes. Studies using P450 form-selective inhibitory antibodies demonstrated that constitutively expressed P450s belonging to subfamily 2C (forms 2C11/2C6) make significant contributions to the activation of both oxazaphosphorines in uninduced male rat liver microsomes, while the phenobarbital-inducible P450 2B1 was shown to be a major catalyst of these activations in phenobarbital-induced microsomes. Pretreatment of rats with dexamethasone increased liver microsomal activation of ifosphamide approximately 6-fold without a corresponding effect on cyclophosphamide activation rates. Ifosphamide activation catalyzed by dexamethasone-induced liver microsomes was minimally inhibited by anti-P450 2B or anti-P450 2C antibodies, but was selectively inhibited by anti-P450 3A antibodies. Selective inhibition of liver microsomal ifosphamide activation was also effected by the macrolide antibiotic triacetyloleandomycin, an inhibitor of several dexamethasone-inducible 3A P450s. These studies establish that a dexamethasone-inducible family 3A P450 can make an important contribution to rat liver microsomal ifosphamide activation, and suggest that dexamethasone pretreatment might provide a useful approach for modulation of ifosphamide metabolism in order to improve its therapeutic efficacy in cancer patients.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies / immunology
  • Biotransformation
  • Cisplatin / pharmacology
  • Clofibrate
  • Cyclophosphamide / metabolism
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / immunology
  • Cytochrome P-450 Enzyme System / metabolism*
  • Dexamethasone
  • Female
  • Ifosfamide / metabolism*
  • Kinetics
  • Male
  • Microsomes, Liver / enzymology*
  • Models, Chemical
  • Phenobarbital
  • Rats
  • Rats, Inbred F344
  • Troleandomycin / pharmacology


  • Antibodies
  • Cytochrome P-450 Enzyme Inhibitors
  • Dexamethasone
  • Cyclophosphamide
  • Cytochrome P-450 Enzyme System
  • Troleandomycin
  • Clofibrate
  • Cisplatin
  • Ifosfamide
  • Phenobarbital