Comparative metabolism of cannabidiol in dog, rat and man

Urinary metabolites of cannabidiol (CBD) were extracted from human, dog and rat urine, concentrated by chromatography on Sephadex LH-20, and identified by GC/MS. Over 50 metabolites were identified with considerable species variation. CBD was excreted in substantial concentration from human urine, both in the free state and as its glucuronide. In dog, unusual glucoside conjugates of three metabolites (4''- and 5''-hydroxy and 6-oxo-CBD), not excreted in the unconjugated state, were found as the major metabolites at early times after drug administration. Other metabolites in all three species were mainly acids. Side-chain hydroxylated derivatives of CBD-7-oic acid were particularly abundant in human urine but much less so in dog. In the latter species the major oxidized metabolites were the products of beta-oxidation with further hydroxylation at C-6. A related, but undefined pathway, resulted in loss of three carbon atoms from the side-chain of CBD in man with the production of 2''-hydroxy-tris,nor-CBD-7-oic acid. Previous experiments indicate that 3'-hydroxy-metabolites are the precursors of compounds having this side-chain. Metabolism by the epoxide-diol pathway, resulting in dihydro-diol formation from the delta-8-double bond, gave metabolites in both dog and human urine. It was concluded that CBD could be used as a probe of the mechanism of several types of biotransformation, particularly those related to carboxylic acid metabolism, as intermediates of the type not usually seen with endogenous compounds were excreted in substantial concentration.