College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan, Canada (A.Z., K.H., A.M.J., N.B., J.C., A.W., A.-M.S., R.B.L.) and Department of Pharmacology, College of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada (R.B.L.).
College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan, Canada (A.Z., K.H., A.M.J., N.B., J.C., A.W., A.-M.S., R.B.L.) and Department of Pharmacology, College of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada (R.B.L.)
J Pharmacol Exp Ther. 2024 Oct 18;391(2):194-205. doi: 10.1124/jpet.123.001998.
Δ-Tetrahydrocannabinol (THC) is a psychoactive phytocannabinoid found in the plant. THC is primarily metabolized into 11-hydroxy-Δ-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-Δ-tetrahydrocannabinol (COOH-THC), which may themselves be psychoactive. There is very little research-based evidence concerning the pharmacokinetics and pharmacodynamics of 11-OH-THC as an individual compound. Male C57BL/6 mice were treated with THC or 11-OH-THC via intraperitoneal injection, tail vein intravenous injection, or oral gavage, and whole-blood compound levels were measured to determine pharmacokinetic parameters [C, time to C (T), elimination half-life, area under the curve, apparent volume of distribution, systemic clearance, terminal rate constant, and absolute bioavailability] while also monitoring changes in catalepsy, body temperature, and nociception. 11-OH-THC achieved a T at 30 minutes for all routes of administration. The maximum concentration at 30 minutes was not different between intravenous and intraperitoneal routes, but the oral gavage C was significantly lower. THC had a 10-minute time to the maximum concentration, which was the first blood collection time point, for intravenous and intraperitoneal and 60 minutes for oral gavage, with a lower C for intraperitoneal and oral gavage compared with intravenous. When accounting for circulating compound levels and ED responses, these data suggest that 11-OH-THC was 153% as active as THC in the tail-flick test of nociception and 78% as active as THC for catalepsy. Therefore, 11-OH-THC displayed equal or greater activity than the parent compound THC, even when accounting for pharmacokinetic differences. Thus, the THC metabolite 11-OH-THC likely plays a critical role in the bioactivity of cannabis; understanding its activity when administered directly will aid in the interpretation of future animal and human studies. SIGNIFICANCE STATEMENT: This study establishes that the primary metabolite of THC, 11-OH-THC, displays equal or greater activity than THC in a mouse model of cannabinoid activity when directly administered and even when accounting for route of administration, sex, pharmacokinetic, and pharmacodynamic differences. These data provide critical insight into the bioactivity of THC metabolites that will inform the interpretation of future in vivo cannabinoid research and represent a model for how THC consumption and metabolism may affect cannabis use in humans.
Δ-四氢大麻酚（THC）是一种存在于大麻植物中的精神活性植物大麻素。THC 主要代谢为 11-羟基-Δ-四氢大麻酚（11-OH-THC）和 11-去甲-9-羧酸-Δ-四氢大麻酚（COOH-THC），它们本身可能具有精神活性。关于作为单一化合物的 11-OH-THC 的药代动力学和药效学，几乎没有基于研究的证据。雄性 C57BL/6 小鼠通过腹腔注射、尾静脉静脉注射或口服灌胃给予 THC 或 11-OH-THC，测量全血化合物水平以确定药代动力学参数[C、达到 C 的时间（T）、消除半衰期、曲线下面积、表观分布体积、全身清除率、末端速率常数和绝对生物利用度]，同时监测僵住、体温和痛觉的变化。所有给药途径的 11-OH-THC 在 30 分钟时达到 C。静脉内和腹腔内途径的最大浓度在 30 分钟时没有差异，但口服灌胃的 C 明显较低。THC 静脉内和腹腔内的最大浓度时间为 10 分钟，是第一次采血时间点，而口服灌胃的时间为 60 分钟，与腹腔内和口服灌胃相比，C 较低。当考虑到循环化合物水平和 ED 反应时，这些数据表明，11-OH-THC 在尾部闪烁测试中对痛觉的活性是 THC 的 153%，对僵住的活性是 THC 的 78%。因此，即使考虑到药代动力学差异，11-OH-THC 也显示出与母体化合物 THC 同等或更高的活性。因此，大麻素代谢物 11-OH-THC 可能在大麻素的生物活性中发挥关键作用；了解其直接给药时的活性将有助于解释未来的动物和人体研究。意义声明：本研究表明，THC 的主要代谢物 11-OH-THC 在直接给药的情况下，即使在考虑给药途径、性别、药代动力学和药效学差异的情况下，其活性也与 THC 在大麻素活性的小鼠模型中相等或更高。这些数据为 THC 代谢物的生物活性提供了重要的见解，将为未来体内大麻素研究的解释提供信息，并代表了 THC 消耗和代谢如何影响人类使用大麻的模型。
