Premium
Isolation from pig liver microsomes, identification by electrospray tandem mass spectrometry and in vitro immunosuppressive activity of a rapamycin tris‐epoxide metabolite
Author(s) -
Lhoëst G.,
Zey T.,
Verbeeck R. K.,
Wallemacq P.,
Maton N.,
De Houx J. P.,
Latinne D.
Publication year - 1999
Publication title -
journal of mass spectrometry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 121
eISSN - 1096-9888
pISSN - 1076-5174
DOI - 10.1002/(sici)1096-9888(199901)34:1<28::aid-jms747>3.0.co;2-#
Subject(s) - chemistry , metabolite , microsome , tandem mass spectrometry , effector , biochemistry , fkbp , in vitro , stereochemistry , mass spectrometry , chromatography
Abstract It was demonstrated that rapamycin is metabolized in vitro by pig liver microsomes under the influence of the cytochromeP450‐dependent mixed function oxygenase system to a rapamycintris‐epoxide metabolite, as demonstrated by electrospraytandem mass spectrometry . The in vitro immunosuppressiveactivity of this metabolite was found to be lower than that ofrapamycin, probably because the rapamycin effector sector wasstructurally modified. The effector region of rapamycin wasrecognized to include the conjugated double bonds of this compoundand metabolic reactions affecting this region may change the bindingaffinity of the rapamycin–FKBP binary complex towards anotherpharmacological receptor bound to the binary complex. Moreover,metabolic modifications in the effector region are probably able toinduce a change in the binding affinities of the rapamycin–FKBPbinary complex, including the pipecolic acid moiety and the lactonefunction of the parent drug. Copyright © 1999 John Wiley &Sons, Ltd.