(M1230-06-35) Pharmacokinetic Study of Delta-8-Tetrahydrocannabinol in Male Rats Using a Validated UPLC-MS/MS Method

Purpose: Cannabis sativa (cannabis) has been recognized as one of the oldest cultivated plant species, and known for its use in medicinal, recreational, and religious purposes¹. The plant contains a number of biologically active compounds, including the most popular cannabinoids; cannabidiol (CBD) and delta-9-tetrahydrocannabinol (Δ9THC)^2,3. An isomer of Δ9THC, delta-8-tetrahydrocannabinol (Δ8THC), has been growing in popularity for its potential therapeutic benefits and its mild psychoactive effects⁴. Surveys have shown that ~11% of 12^th-grade students have reported the use of Δ8THC, as well as Δ8THC being commonly used in states that do not have cannabis legalization or Δ8THC regulations⁵. In the United States (US), there has been much debate regarding the regulatory status of Δ8THC, and a gap in knowledge of whether this compound is safe and similar in pharmacokinetics to Δ9THC^6,7. Due to these circumstances, a single-dose pharmacokinetic study in male Sprague-Dawley rats, was performed.

Methods: A bioanalytical method was validated using FDA M10 bioanalytical guidelines⁸ and used to determine the concentrations of Δ8THC, and its metabolites, 11-hydroxy-Δ8THC (11OH-Δ8THC) and 11-carboxy-Δ8THC (11COOH-Δ8THC) in rat plasma. Single-dose pharmacokinetic studies of Δ8THC were performed following an oral (7.5 mg/kg) and intravenous (1.25 mg/kg) administration (N=3 and N=4, respectively) in male Sprague-Dawley rats. Blood samples were collected pre-dose, and 0.08, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 18, and 24 h, post-dose. Blood was centrifuged at 1500 rpm for 10 min at 4˚C to collect plasma for analysis. The results were then subjected to non-compartmental analysis using Phoenix^® 6.4 (Certara) to determine pharmacokinetic parameters.

Results: After intravenous administration, Δ8THC had a clearance of 5.6 ± 0.4 L/h/kg which was higher than rat hepatic blood flow (4.8 L/h/kg)⁹ indicating extrahepatic clearance, as well as a large volume of distribution (V_ss, 28.7 ± 2.8 L/kg) indicating extravascular distribution. The elimination half-life of Δ8THC was 14.3 ± 3.5 h. A study performed by Ravula et al¹⁰, reported after intravenous administration of Δ9THC, clearance was lower than Δ8THC, at 3.1 ± 0.0 L/h/kg, volume of distribution (V_ss) was 10.3 ± 0.6 L/kg, and elimination half-life was 1.9 ± 0.3 h, which shows that Δ8THC pharmacokinetic parameters are different than Δ9THC. The metabolite C_max after intravenous administration were 55.2 ± 14.9 ng/mL (T_max = 0.8 ± 0.0 h) and 76.4 ± 11.3 ng/mL (T_max = 0.8 ± 0.1 h) for 11OH-Δ8THC and 11COOH-Δ8THC, respectively. Following an oral administration of Δ8THC, C_max/dose (peak plasma concentration corrected for dose) was 1.8 ± 0.3 ng/mL, and T_max (time to reach C_max) was 0.5 ± 0.3 h.

Conclusion: The validated bioanalytical method was used successfully to determine concentration-time profile of Δ8THC, and its metabolites, 11OH-Δ8THC and 11COOH-Δ8THC in rat plasma following the pharmacokinetic studies. Based on previous literature¹⁰, it seems that Δ8THC and Δ9THC pharmacokinetic parameters are not similar, due to a low clearance and volume of distribution shown after intravenous administration of Δ9THC. We were able to quantify metabolites of Δ8THC in rat plasma after both oral and intravenous dose up to 24 h post-dose. Overall, Δ8THC had high clearance and large volume of distribution which indicate extensive tissue distribution with contribution of extrahepatic clearance.

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