1: Xenobiotica 1997 Sep;27(9):869-83
Isolation and identification of new rapamycin dihydrodiol metabolites from
dexamethasone-induced rat liver microsomes.
Nickmilder MJ, Latinne D, Verbeeck RK, Janssens W, Svoboda D, Lhoest GJ
Department of Pharmaceutical Sciences-UCL, Pharmacokinetics and Metabolism
Unit Laboratory of Mass Spectrometry, Brussels, Belgium.
1. Rapamycin is metabolically transformed in rat liver microsomes to 3,4-
and 5,6-dihydrodiol metabolites under the influence of the cytochrome P-450
mixed function oxygenase system. These metabolites were produced from dexamethasone-induced
as well as from non-induced rat liver microsomes. The comparison of the
ion spray mass spectra of the 5,6-dihydrodiol with the 3,4-dihydrodiol
of rapamycin shows clearly that dihydrodiols were formed in two distinct
positions of rapamycin. 2. FAB mass spectra as well as electrospray mass
spectra of two additional peaks isolated from the same chromatographic
run confirm the presence of a 3,4-dihydrodiol metabolite of rapamycin as
also strongly suggested by UV spectra. Hplc reinjection of each individual
peak always resulted in chromatograms showing a combination of the same
three peaks and therefore are to be considered as tautomers of the 3,4-dihydrodiol
of rapamycin. 3. These tautomeric conformations were found to have no immunosuppressive
potency, most probably due to important structural and stereochemical modifications
of the rapamycin binding domain to the binding protein (FKBP-12) and/or
to important metabolic structural modifications of rapamycin effector domain.
PMID: 9381729, UI: 98018121