PT - JOURNAL ARTICLE AU - Christians, U AU - Sattler, M AU - Schiebel, H M AU - Kruse, C AU - Radeke, H H AU - Linck, A AU - Sewing, K F TI - Isolation of two immunosuppressive metabolites after in vitro metabolism of rapamycin. DP - 1992 Mar 01 TA - Drug Metabolism and Disposition PG - 186--191 VI - 20 IP - 2 4099 - http://dmd.aspetjournals.org/content/20/2/186.short 4100 - http://dmd.aspetjournals.org/content/20/2/186.full SO - Drug Metab Dispos1992 Mar 01; 20 AB - Rapamycin was incubated with human liver microsomes and an NADPH regenerating system, the metabolites were purified by semipreparative HPLC, and their structures were elucidated by direct chemical ionization and FAB-MS. At least six fractions were isolated containing rapamycin metabolites, indicating that rapamycin is metabolized by the human liver cytochrome P-450 system. One of these metabolites was identified as 41-O-demethyl-rapamycin. A second metabolite was hydroxylated in a yet unknown position. These two metabolites retained immunosuppressive activity in a phytohemagglutinin-stimulated human lymphocyte assay with IC50S of 1 and 1.5 nmol/liter, respectively. Rapamycin was metabolized by rat small intestinal microsomes to at least two metabolites, indicating extra-hepatic metabolism of rapamycin.