Isolation, identification and immunosuppressive activity of SDZ-IMM-125 metabolites from human liver microsomes.
SDZ-IMM-125 N-methyl leucine 9 hydroxylated in the gamma position is a metabolite which was extracted from incubated human liver microsomes and subsequently separated by normal and reverse-phase HPLC. This metabolite was identified by fast atom bombardment mass spectrometry, electrospray-ms/ms mass spectrometry and nuclear magnetic resonance spectroscopy. The in vitro 50% inhibitory concentration, tested against bidirectional mixed lymphocyte reaction was 80 microg/l indicating that this metabolite does not retain in vitro immunosuppressive activity most probably due to the structural modification of SDZ-IMM-125 in the recognized binding region to cyclophilin A reducing its binding affinity relative to the parent drug.
Department of Pharmaceutical Sciences-UCL, Pharmacokinetics and Metabolism Unit-FATC Laboratory of Mass Spectrometry, Brussels, Belgium.
R
R
Dieden
R K
RK
Verbeeck
D
D
Latinne
P
P
Wallemacq
N
N
Maton
G J
GJ
Lhoest
D001665:Binding Sites; D002851:Chromatography, High Pressure Liquid; D003524:Cyclosporins / Q000276:immunology* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007166:Immunosuppressive Agents / Q000302:isolation & purification / Q000494:pharmacology*; D066298:In Vitro Techniques; D008214:Lymphocytes / Q000187:drug effects*; D008862:Microsomes, Liver / Q000737:chemistry*; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D013057:Spectrum Analysis
D003524:Cyclosporins; D007166:Immunosuppressive Agents; D019696:Peptidylprolyl Isomerase; C075935:SDZ IMM 125