Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Δ9-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive-compulsive behaviour
Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Δ9-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive-compulsive behaviour
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DOI：
10.1007/s00213-011-2415-0
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发表时间：
2012-02-01
影响因子：
3.4
通讯作者：
Riedel, Gernot
中科院分区：
文献类型：
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作者：
Deiana, Serena;Watanabe, Akihito;Riedel, Gernot
植物大麻素是用于多种应用的有用治疗剂，包括治疗便秘、疟疾、风湿病、减轻眼内压、呕吐、焦虑和一些神经和神经变性疾病。与这些药用特性一致，提取的大麻素最近在研究中引起了很大的兴趣，其中一些目前处于临床试验的后期阶段。然而，大麻植物Cannabis sativa的其他成分在体内仍然相对未被探索。这些植物大麻素包括大麻二酚（cannabidiol，CBD）、大麻二酚（cannabidivarine，CBDV）、δ（9）-四氢大麻二酚（Delta（9）-THCV）和大麻萜酚（cannabigerol，CBG）。CBD（120 mg/kg，ip和口服）的药效学-药代动力学关系使用小鼠中的大理石掩埋试验进一步评估。所有植物大麻素容易穿透血脑屏障和solutol，尽管产生适度的行为异常，但在口服后导致比cremophor更高的脑渗透，而不是腹膜内暴露。在小鼠中，基于克列莫佛的腹膜内给药总是获得较高的血浆和脑浓度，与给予的物质无关。在大鼠中，口服给药提供了CBD（120 mg/kg）和CBDV（60 mg/kg）的更高脑浓度，但Delta（9）-THCV（30 mg/kg）和CBG（120 mg/kg）没有，腹腔内途径更有效。CBD抑制强迫行为的时间依赖性的方式匹配其药代动力学profile.These数据提供了重要的信息大脑和血浆暴露的新的植物大麻素和指导最有效的管理途径和时间点，在体内条件下确定药物的效果。
Phytocannabinoids are useful therapeutics for multiple applications including treatments of constipation, malaria, rheumatism, alleviation of intraocular pressure, emesis, anxiety and some neurological and neurodegenerative disorders. Consistent with these medicinal properties, extracted cannabinoids have recently gained much interest in research, and some are currently in advanced stages of clinical testing. Other constituents of Cannabis sativa, the hemp plant, however, remain relatively unexplored in vivo. These include cannabidiol (CBD), cannabidivarine (CBDV), Delta(9)-tetrahydrocannabivarin (Delta(9)-THCV) and cannabigerol (CBG).We here determined pharmacokinetic profiles of the above phytocannabinoids after acute single-dose intraperitoneal and oral administration in mice and rats. The pharmacodynamic-pharmacokinetic relationship of CBD (120 mg/kg, ip and oral) was further assessed using a marble burying test in mice.All phytocannabinoids readily penetrated the blood-brain barrier and solutol, despite producing moderate behavioural anomalies, led to higher brain penetration than cremophor after oral, but not intraperitoneal exposure. In mice, cremophor-based intraperitoneal administration always attained higher plasma and brain concentrations, independent of substance given. In rats, oral administration offered higher brain concentrations for CBD (120 mg/kg) and CBDV (60 mg/kg), but not for Delta(9)-THCV (30 mg/kg) and CBG (120 mg/kg), for which the intraperitoneal route was more effective. CBD inhibited obsessive-compulsive behaviour in a time-dependent manner matching its pharmacokinetic profile.These data provide important information on the brain and plasma exposure of new phytocannabinoids and guidance for the most efficacious administration route and time points for determination of drug effects under in vivo conditions.