Pharmacokinetic study of delta-8-tetrahydrocannabinol in male rats using a validated bioanalytical method.

Delta-8-THC, a cannabinoid growing in popularity for its reported therapeutic effects, was studied in male rats to understand its pharmacokinetics. After a single oral dose of 7.5 mg/kg, the compound showed very low oral bioavailability of 3.0%, with a peak plasma concentration of 13.4 ng/mL reached in 0.5 hours. Intravenous dosing at 1.25 mg/kg revealed a clearance rate higher than rat liver blood flow, suggesting elimination occurs partly outside the liver, and a large volume of distribution, indicating extensive movement into tissues. The elimination half-life was 13.9 hours. These findings suggest that oral Delta-8-THC is poorly absorbed, while its distribution and clearance patterns resemble those of other cannabinoids.

Study at a glance

Abstract

Delta-8-tetrahydrocannabinol (Δ8THC) has been growing in popularity across the United States due to its reported therapeutic benefits, including pain relief, euphoria, relaxation, and mild psychoactive effects, especially in areas where sale of delta-9-tetrahydrocannabinol (Δ9THC) is illegal. Currently, much debate surrounds Δ8THC regarding its regulatory status and whether this compound is safe and similar in pharmacokinetics to Δ9THC. To address the latter issue, a single-dose oral (7.5 mg/kg) and intravenous (IV; 1.25 mg/kg) pharmacokinetic study was performed in male Sprague-Dawley rats. A bioanalytical method was developed and validated following the FDA M10 guidelines in rat plasma to detect Δ8THC and its metabolites, 11-hydroxy-delta-8-tetrahydrocannabinol (11OH-Δ8THC) and 11-carboxy-delta-8-tetrahydrocannabinol (11COOH-Δ8THC). This method was then applied to analyze the plasma samples collected during the preclinical pharmacokinetic studies. The plasma concentration-time profiles were subjected to non-compartmental analysis to obtain pharmacokinetic parameters. When administered intravenously, Δ8THC had a clearance of 5.6 ± 0.4 L/h/kg, a volume of distribution of 108.4 ± 8.9 L/kg, and elimination half-life of 13.9 ± 2.0 h. Δ8THC pharmacokinetic parameters following oral administration, exhibited a Cmax (peak plasma concentration) of 13.4 ± 0.9 ng/mL with a Tmax (time to reach Cmax) of 0.5 ± 0.1 h, and an oral bioavailability of 3.0 ± 0.3%. The clearance of Δ8THC when dosed IV is higher than rat hepatic blood flow (4.8 L/h/kg), indicative of extrahepatic clearance. Δ8THC also had a large volume of distribution, indicating extravascular distribution. Overall, Δ8THC had very low oral bioavailability, while the clearance and volume of distribution values indicate extensive tissue distribution with contribution of extrahepatic clearance.