Metabolism of cannabidiol by the rat

Metabolites of CBD excreted into the bile and perfusion fluid were examined in a rat liver perfusion preparation. Metabolites were extracted with ethyl acetate and identified by GC/MS as TMS derivatives. Four mono- and five di-hydroxy metabolites were identified with major sites of metabolic attack being at C-7 and C-4″. A hydroxy-ketone was detected but not fully identified. All biliary metabolites were conjugated with glucuronic acid. Urinary metabolites were studied in rats with samples taken at times to 25 h after drug administration. Unmetabolized CBD and 13 metabolites were identified by GC/MS. Major metabolites were acids with beta-oxidation being a prominent pathway. The 6- and 7-hydroxy derivatives of 4″, 5″-bis,nor-CBD-3″-oic acid were the most abundant compounds but substantial concentrations of the di-acids, CBD-5″,7-dioic acid and 4″,5″-bis,nor-CBD-3″,7-dioic acid were present. Concentrations of the more highly oxidized metabolites increased with time.