Identification of urinary metabolites of cannabidiol in the dog

Three dogs were treated with cannabidiol (CBD) and urine samples were collected periodically to 30 hr. Metabolites were extracted with ethyl acetate before and after hydrolysis with β-glucuronidase, and examined by GC/MS. Thirty-seven metabolites were identified and a further nine partially characterized. Twenty-one of the identified metabolites have not been reported for this drug. The major oxidative metabolic routes were 6-hydroxylation, both α and β, and β-oxidation. At 10 hr the major metabolites of this type were 6-hydroxy-4'',5''-bis,nor-CBD-3''-oic acid and 6-oxo-4'',5''-bis,nor-CBD-3''-oic acid, whereas at 22 hr, further β-oxidation had occurred to give 6-hydroxy-2'',3'',4'',5''-tetrakis,nor-CBS-1''pr-oic acid as the major metabolite. Other metabolic routes were carboxylic acid formation at C-7 accompanied by hydroxylation in the side chain, and dihydroxylation of the C-8,9 double bond. Three compounds, 4''-hydroxy-CBD, 5'hydroxy-CBD, and 6-oxo-CBD were found at early times as glucose conjugates in concentrations that exceeded those of the other metabolites. The unconjugated forms of these metabolites were not found and none of the identified oxidized metabolites were found as glucosides. Only 4'',6-dihydroxy-CBD was found conjugated with glucuronic acid.