15-Desmethyl FK-506 and 15,31-desmethyl FK-506 from human liver microsomes: isolation, identification (by fast atom bombardment mass spectrometry and NMR), and evaluation of in vitro immunosuppressive activity.
15-Desmethyl FK-506 and 15,31-desmethyl FK-506 metabolites extracted from incubated human liver microsomes were separated by normal and reversed-phase HPLC. The metabolites were identified by fast atom bombardment/mass spectrometry and nuclear magnetic resonance spectroscopy. The in vitro 50% inhibitory concentration, tested against bidirectional mixed lymphocyte reactions, was 325 mg/L for 15,31-desmethyl FK-506 and 4 mg/L for 15-desmethyl FK-506, indicating that these products of FK-506 demethylation retain in vitro immunosuppressive activity.
Lhöest
G J
GJ
Department of Pharmaceutical Sciences, UCL, FATC, Brussels, Belgium.
Maton
N
N
Latinne
D
D
Laurent
A
A
Verbeeck
R K
RK
D002851:Chromatography, High Pressure Liquid; D006801:Humans; D007165:Immunosuppression Therapy; D007959:Lymphocyte Culture Test, Mixed; D009682:Magnetic Resonance Spectroscopy; D008745:Methylation; D008862:Microsomes, Liver / Q000737:chemistry*; D016339:Spectrometry, Mass, Fast Atom Bombardment; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology
C087154:15,31-desmethyl FK-506; C087153:15-desmethyl FK-506; D016559:Tacrolimus