Isolation, identification and immunosuppressive activity of SDZ-IMM-125 metabolites from human liver microsomes

Eur J Drug Metab Pharmacokinet. 1999 Jan-Mar;24(1):83-90. doi: 10.1007/BF03190015.

Abstract

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.

MeSH terms

  • Binding Sites
  • Chromatography, High Pressure Liquid
  • Cyclosporins / immunology*
  • Cyclosporins / metabolism*
  • Dose-Response Relationship, Drug
  • Humans
  • Immunosuppressive Agents / isolation & purification
  • Immunosuppressive Agents / pharmacology*
  • In Vitro Techniques
  • Lymphocytes / drug effects*
  • Microsomes, Liver / chemistry*
  • Peptidylprolyl Isomerase / metabolism*
  • Spectrum Analysis

Substances

  • Cyclosporins
  • Immunosuppressive Agents
  • Peptidylprolyl Isomerase
  • SDZ IMM 125