1: Clin Chem 1998 Mar;44(3):532-8
Isolation and identification of a C39 demethylated metabolite of rapamycin
from pig liver microsomes and evaluation of its immunosuppressive activity.
Nickmilder MJ, Latinne D, De Houx JP, Verbeeck RK, Lhoest GJ
Department of Pharmaceutical Sciences-UCL, Brussels, Belgium.
We studied in vitro metabolism of rapamycin using pig liver microsomes.
After extraction of the metabolites from the incubation medium, the crude
metabolite extract was submitted to normal and subsequently to reversed-phase
HPLC chromatography. We describe in the current study a metabolite of retention
time 23.2 min collected from reversed-phase HPLC and identified by fast
atom bombardment mass spectrometry (MS) and electrospray MS-MS as a C39
demethylated rapamycin metabolite. In vitro immunosuppressive activity
of this metabolite, determined by the mixed lymphocyte reaction, was negligible
compared with that of the parent compound. The decrease of in vitro immunosuppressive
activity compared with the parent compound is likely to be attributed to
important structural modifications of the rapamycin binding region to the
FK-506 binding protein.
PMID: 9510858, UI: 98171847