This article provides a critical appraisal of the available evidence concerning clinical exposure to orally administered cannabidiol (CBD), with special reference to factors affecting gastrointestinal absorption, presystemic elimination, and susceptibility to metabolic drug interactions. Although detailed studies have not been published, the available data suggest that the absolute bioavailability of CBD after oral dosing under fasting conditions is approximately 6%, and increases fourfold when the medication is co-administered with a high-fat meal. Based on measurements of CBD plasma exposure after oral dosing and a 6% absolute oral bioavailability estimate, the actual clearance of CBD in adults can be inferred to be in the order of 67 L/h, which is similar to the value of 74 ± 14 L/h (mean ± standard deviation) determined after intravenous injection of a 20-mg dose of deuterium-labeled CBD in five healthy subjects. Assuming that the CBD blood-to-plasma ratio is about 1, as in the case of tetrahydrocannabinol (THC), and that CBD metabolism takes place virtually entirely in the liver, it can be estimated that about 70 to 75% of an orally absorbed dose of CBD can be removed by hepatic metabolism before reaching the systemic circulation, and additionally CBD gastrointestinal absorption is incomplete. A formulation with improved biopharmaceutical properties could increase the extent of CBD absorption about fourfold (i.e., to the level achieved with the currently available formulations co-administered with a high-fat meal) and minimize the influence of food effects on CBD bioavailability. There is also potential for favoring the absorption of CBD through the enteric lymphatic system, thereby reducing the extent of presystemic hepatic elimination. Evidence that CBD can behave as a high hepatic clearance compound also has implications when predicting the magnitude of drug–drug interactions affecting CBD metabolism. These considerations have important clinical relevance, particularly with respect to the objective of minimizing pharmacokinetic variability and consequent intra- and interindividual differences in therapeutic response and susceptibility to adverse effects.

本文对有关口服大麻二酚 (CBD) 的临床暴露的现有证据进行了批判性评估，特别提到了影响胃肠道吸收、系统前消除和对代谢药物相互作用的敏感性的因素。虽然详细的研究尚未发表，但现有数据表明，空腹条件下口服 CBD 后的绝对生物利用度约为 6%，当药物与高脂肪餐共同给药时，其绝对生物利用度增加了四倍。根据口服给药后 CBD 血浆暴露的测量值和 6% 的绝对口服生物利用度估计值，可以推断成人 CBD 的实际清除率约为 67 L/h，这与在五名健康受试者中静脉注射 20 毫克剂量的氘标记 CBD 后确定的 74 ± 14 L/h（平均值 ± 标准偏差）的值相似。假设 CBD 血液与血浆的比率约为 1，如四氢大麻酚 (THC) 的情况，并且 CBD 代谢几乎完全在肝脏中进行，可以估计约 70% 至 75% 的口服吸收CBD的剂量在到达体循环前可被肝脏代谢清除，另外CBD胃肠道吸收不完全。具有改进的生物制药特性的制剂可以将 CBD 吸收的程度增加约四倍（即达到目前可用的制剂与高脂肪膳食共同给药的水平），并最大限度地减少食物对 CBD 生物利用度的影响。也有可能通过肠道淋巴系统促进 CBD 的吸收，从而减少系统前肝脏消除的程度。在预测影响 CBD 代谢的药物相互作用的程度时，CBD 可以作为一种高肝脏清除率化合物的证据也具有意义。这些考虑具有重要的临床相关性，特别是在最小化药代动力学变异性和随之而来的治疗反应和不良反应易感性的个体内部和个体间差异的目标方面。在预测影响 CBD 代谢的药物相互作用的程度时，CBD 可以作为一种高肝脏清除率化合物的证据也具有意义。这些考虑具有重要的临床相关性，特别是在最小化药代动力学变异性和随之而来的治疗反应和不良反应易感性的个体内部和个体间差异的目标方面。在预测影响 CBD 代谢的药物相互作用的程度时，CBD 可以作为一种高肝脏清除率化合物的证据也具有意义。这些考虑具有重要的临床相关性，特别是在最小化药代动力学变异性和随之而来的治疗反应和不良反应易感性的个体内部和个体间差异的目标方面。