Isolation from pig liver microsomes, identification by electrospray tandem mass spectrometry and in vitro immunosuppressive activity of a rapamycin tris-epoxide metabolite.

Lhoest G, Zey T, Verbeeck RK, Wallemacq P, Maton N, De Houx JP, Latinne D

Department of Pharmaceutical Sciences, UCL, FATC, Brussels, Belgium.
lhoest@fatc.ucl.ac.be

It was demonstrated that rapamycin is metabolized in vitro by pig liver microsomes under the influence of the cytochrome P450-dependent mixed function oxygenase system to a rapamycin tris-epoxide metabolite, as demonstrated by electrospray tandem mass spectrometry. The in vitro immunosuppressive activity of this metabolite was found to be lower than that of rapamycin, probably because the rapamycin effector sector was structurally modified. The effector region of rapamycin was recognized to include the conjugated double bonds of this compound and metabolic reactions affecting this region may change the binding affinity of the rapamycin-FKBP binary complex towards another pharmacological receptor bound to the binary complex. Moreover, metabolic modifications in the effector region are probably able to induce a change in the binding affinities of the rapamycin-FKBP binary complex, including the pipecolic acid moiety and the lactone function of the parent drug.

PMID: 10028689, UI: 99153043