Division of Clinical and Experimental Pharmacology, Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy.
IRCCS Mondino Foundation, Pavia, Italy.
CNS Drugs. 2020 Aug;34(8):795-800. doi: 10.1007/s40263-020-00741-5.
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.
这篇文章对口服给予的大麻二酚（CBD）的临床暴露相关证据进行了批判性评估，特别关注影响胃肠道吸收、药物前体消除和代谢药物相互作用易感性的因素。尽管尚未发表详细研究，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%，当药物与高脂肪餐同时给药时，其生物利用度增加四倍。基于口服给药后 CBD 血浆暴露的测量值和 6%的绝对口服生物利用度估计值，可以推断出成人 CBD 的实际清除率约为 67 L/h，与静脉注射 20mg 氘标记 CBD 后在五名健康受试者中确定的 74±14 L/h（平均值±标准差）值相似。假设 CBD 的血-血浆比大约为 1，就像四氢大麻酚（THC）一样，并且 CBD 代谢几乎完全在肝脏中进行，可以估计，大约 70%至 75%的口服吸收剂量的 CBD 在到达体循环之前可以通过肝代谢去除，此外 CBD 的胃肠道吸收不完全。具有改善的生物制药特性的制剂可以使 CBD 的吸收程度增加约四倍（即，达到目前市售制剂与高脂肪餐同时给药的水平），并最大程度地减少食物对 CBD 生物利用度的影响。还有可能通过肠淋巴系统促进 CBD 的吸收，从而减少药物前体消除的程度。CBD 可以表现为高肝清除化合物的证据也对影响 CBD 代谢的药物相互作用的程度预测具有重要的临床意义。这些考虑因素具有重要的临床意义，特别是在最小化药代动力学变异性和因此治疗反应和不良反应易感性的个体内和个体间差异的目标方面。
