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

✍ Scribed by Lhoëst, G.; Zey, T.; Verbeeck, R. K.; Wallemacq, P.; Maton, N.; De Houx, J. P.; Latinne, D.

• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: English
• Weight: 111 KB
• Volume: 34
• Category: Article
• ISSN: 1076-5174
• DOI: 10.1002/(sici)1096-9888(199901)34:1<28::aid-jms747>3.0.co;2-#

✦ Synopsis

It was demonstrated that rapamycin is metabolized in vitro by pig liver microsomes under the inÑuence 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 e †ector sector was structurally modi-Ðed. The e †ector region of rapamycin was recognized to include the conjugated double bonds of this compound and metabolic reactions a †ecting this region may change the binding affinity of the rapamycin-FKBP binary complex towards another pharmacological receptor bound to the binary complex. Moreover, metabolic modiÐcations in the e †ector 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.