Pharmacokinetics of cannabidiol and its metabolites in rhesus monkeys and New Zealand White rabbits

Cannabidiol (CBD) is extensively metabolized in humans, with 7-carboxy-CBD being the major metabolite. The biotransformation of CBD in mice, rats, and dogs differs from that in humans. We have investigated if the pharmacokinetics of CBD in rhesus monkeys and New Zealand White rabbits is similar to humans by measuring serum levels of CBD and its phase I and II metabolites after single intragastric (77.5 mg/kg body weight) or intravenous (3.9 mg/kg body weight) CBD doses. In rhesus monkeys, intragastric CBD yielded a maximum concentration (Cmax) of 241.6 nM (males) and 476.5 nM (females), with a terminal half-life (T1/2) of 11.6 and 15.4 h. The area under the curve from zero to infinity (AUC0-inf) was 5,376 nM*h (males) and 7,366 nM*h (females), with bioavailability of 2.5% and 5.5%. 7-Carboxy-CBD showed a Cmax of 334.7 nM (males) and 655.4 nM (females), with AUC0-inf 1.5 to 1.6 times higher than CBD. The levels of other metabolites were minimal. In rabbits, intragastric CBD resulted in a Cmax of 76.6 nM (males) and 117.1 nM (females), with a T1/2 of 11.1 and 14.9 h. The AUC0-inf was 1,443 nM*h (males) and 1,645 nM*h (females), with bioavailability of 2.1% to 2.2%. 7-Carboxy-CBD levels were significantly higher than CBD, with a Cmax of 11,631 nM (males) and 13,278 nM (females), and an AUC0-inf 120 to 133 times higher. In contrast to rhesus monkeys, New Zealand White rabbits exhibit a CBD metabolic profile similar to humans, with high levels of 7-carboxy-CBD, making them a promising model for studying CBD metabolism-driven toxicity.