Evaluation of Cytochrome P450-Mediated Cannabinoid-Drug Interactions in Healthy Adult Participants.
Evaluation of Cytochrome P450-Mediated Cannabinoid-Drug Interactions in Healthy Adult Participants.
复制标题
健康成人参与者中细胞色素 P450 介导的大麻素-药物相互作用的评估。
DOI：
10.1002/cpt.2973
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发表时间：
2023
影响因子：
6.7
通讯作者：
Unadkat,JashvantD
中科院分区：
文献类型：
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作者：
Bansal,Sumit;Zamarripa,CAustin;Spindle,ToryR;Weerts,EliseM;Thummel,KennethE;Vandrey,Ryan;Paine,MaryF;Unadkat,JashvantD
了解大麻药物相互作用至关重要，因为监管变化增加了大麻的获得和使用。大麻二酚（CBD）和Δ-9-四氢大麻酚（Δ9-THC）是最丰富的植物大麻素，是几种细胞色素P450（CYP）酶的体外可逆和时间依赖性（仅CBD）抑制剂。大麻提取物用于定量评估18名健康成人中大麻素-药物相互作用的潜在药代动力学。参与者以随机交叉方式（间隔≥ 1周）接受含有（i）无大麻提取物（乙醇/安慰剂），（ii）CBD-主要大麻提取物（640 mg CBD + 20 mg Δ9-THC）或（iii）Δ9-THC-主要大麻提取物（20 mg Δ9-THC且无CBD）的布朗尼。30分钟后，参与者服用细胞色素P450（CYP 1A 2），氯沙坦（CYP 2C 9），奥美拉唑（CYP 2C 19），美沙芬（CYP 2D 6）和咪达唑仑（CYP 3A）组成的药物鸡尾酒。采集血浆和尿液样本（0-24小时）。CBD + Δ9-THC布朗尼抑制CYP 2C 19> CYP 2C 9> CYP 3A> CYP 1A 2（但不抑制CYP 2D 6）活性，表现为奥美拉唑、氯沙坦、咪达唑仑和咖啡因的血浆浓度-时间曲线下面积（AUC）相对于安慰剂（AUCGMR）的几何平均比值分别增加207%、77%、56%和39%。相比之下，Δ9-THC布朗尼不抑制任何CYP。CBD + Δ9-THC布朗尼使Δ9-THC AUCGMR增加161%，与CBD抑制CYP 2C 9介导的口服Δ9-THC清除一致。除咖啡因外，我们基于生理学的药代动力学模型很好地预测了这些相互作用（在观察到的相互作用的26%以内）。结果可用于帮助指导与大麻产品共同消费的药物的剂量调整以及大麻产品中CBD的剂量，以降低与Δ9-THC的相互作用风险。
Understanding cannabis‐drug interactions is critical given regulatory changes that have increased access to and use of cannabis. Cannabidiol (CBD) and Δ‐9‐tetrahydrocannabinol (Δ9‐THC), the most abundant phytocannabinoids, arein vitroreversible and time‐dependent (CBD only) inhibitors of several cytochrome P450 (CYP) enzymes. Cannabis extracts were used to evaluate quantitatively potential pharmacokinetic cannabinoid‐drug interactions in 18 healthy adults. Participant received, in a randomized cross‐over manner (separated by ≥ 1 week), a brownie containing (i) no cannabis extract (ethanol/placebo), (ii) CBD‐dominant cannabis extract (640 mg CBD + 20 mg Δ9‐THC), or (iii) Δ9‐THC‐dominant cannabis extract (20 mg Δ9‐THC and no CBD). After 30 minutes, participants consumed a cytochrome P450 (CYP) drug cocktail consisting of caffeine (CYP1A2), losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A). Plasma and urine samples were collected (0–24 hours). The CBD + Δ9‐THC brownie inhibited CYP2C19 > CYP2C9 > CYP3A > CYP1A2 (but not CYP2D6) activity, as evidenced by an increase in the geometric mean ratio of probe drug area under the plasma concentration‐time curve (AUC) relative to placebo (AUCGMR) of omeprazole, losartan, midazolam, and caffeine by 207%, 77%, 56%, and 39%, respectively. In contrast, the Δ9‐THC brownie did not inhibit any of the CYPs. The CBD + Δ9‐THC brownie increased Δ9‐THC AUCGMRby 161%, consistent with CBD inhibiting CYP2C9‐mediated oral Δ9‐THC clearance. Except for caffeine, these interactions were well‐predicted by our physiologically‐based pharmacokinetic model (within 26% of observed interactions). Results can be used to help guide dose adjustment of drugs co‐consumed with cannabis products and the dose of CBD in cannabis products to reduce interaction risk with Δ9‐THC.