In vitro metabolism of FK-506 in rat, rabbit, and human liver microsomes: identification of a major metabolite and of cytochrome P450 3A as the major enzymes responsible for its metabolism

Arch Biochem Biophys. 1992 May 1;294(2):454-60. doi: 10.1016/0003-9861(92)90711-5.


The metabolism of the immunosuppressant FK-506 was shown to be catalyzed primarily by cytochrome P450 isozymes of the P450 3A subfamily. Antibodies against rat P450 3A inhibited FK-506 metabolism by 82% in rat liver microsomes and by 35-56% in liver microsomes from humans, dexamethasone-induced rats, and erythromycin-induced rabbits. Poor species cross-reactivity of the antibodies, metabolic switching, and/or some metabolism by P450 isozymes other than P450 3A may be responsible for the incomplete inhibition observed. Besides anti-rat P450 3A, antibodies against rat P450 1A also appeared to have some inhibitory effect implicating these particular cytochrome P450 isozymes as having a minor role in FK-506 metabolism. The formation of 13-desmethyl FK-506, identified here as a major metabolite of FK-506 in all types of microsomes examined, was inhibited completely by anti-P450 3A in liver microsomes from dexamethasone-induced rats and erythromycin-induced rabbits but only partially in human and control rat liver microsomes.

MeSH terms

  • Adult
  • Animals
  • Antibodies
  • Biotransformation
  • Carbon Radioisotopes
  • Cytochrome P-450 CYP2E1
  • Cytochrome P-450 Enzyme System / metabolism*
  • Dexamethasone / pharmacology
  • Female
  • Humans
  • Kinetics
  • Male
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology*
  • Mixed Function Oxygenases / metabolism*
  • Proadifen / pharmacology
  • Rabbits
  • Rats
  • Rats, Inbred Strains
  • Tacrolimus / metabolism*
  • Troleandomycin / pharmacology


  • Antibodies
  • Carbon Radioisotopes
  • Dexamethasone
  • Cytochrome P-450 Enzyme System
  • Proadifen
  • Troleandomycin
  • Mixed Function Oxygenases
  • Cytochrome P-450 CYP2E1
  • Tacrolimus