High Performance Liquid Chromatographic Isolation and Spectroscopic Characterization of Three Major Metabolites from the Plasma of Rats Receiving Rapamycin (Sirolimus) Orally

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Abstract
Three major metabolites of rapamycin (M2, M3, and M5) were isolated from pooled plasma of orally dosed rats. Metabolites were extracted from the plasma with ethyl acetate/methanol prior to isolation by HPLC using a Supelcosil SPLC-18, 5μm, 10 × 250 mm column. The mobile phase was a methanol/ammonium acetate linear gradient system. The isolated metabolites were characterized by negative ion FAB MS, ion-spray MS and ion-spray MS/MS. Metabolite M2 is oxygenated in the southern portion of rapamycin and the macrolide ring is opened. M3 is a structural isomer of rapamycin where the lactone ring is opened. M5 is O-demethylated on the C41 methoxy moiety and the macrolide ring is intact.