Validation of Large White Pig as an animal model for the study of cannabinoids metabolism:: Application to the study of THC distribution in tissues
Validation of Large White Pig as an animal model for the study of cannabinoids metabolism:: Application to the study of THC distribution in tissues
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DOI：
10.1016/j.forsciint.2006.04.018
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发表时间：
2006-09-12
影响因子：
2.2
通讯作者：
Mura, Patrick
中科院分区：
文献类型：
--
作者：
Brunet, Bertrand;Doucet, Carole;Mura, Patrick
本研究提出了一种新的动物模型，大白色猪，这是测试研究大麻素代谢。第一步集中于在以不同剂量注射Delta（9）-四氢大麻酚（THC）后测定血浆动力学。七头猪通过静脉注射接受THC（50、100或200 μ g/kg）。在48小时内收集血浆样品。通过气相色谱/质谱法进行大麻素浓度的测定。结果表明，血浆动力学与人体中报告的动力学相当。终末消除半衰期为10.6 h，计算的分布容积为321/kg。在第二步中，该模型用于确定大麻素在组织中分布的动力学曲线。八只大白色雄性猪接受THC注射（200 μ g/kg）。注射后30 min处死2头猪，2、6和24 h处死2头猪。采集不同组织样本：肝脏、肾脏、心脏、肺、脾脏、肌肉、脂肪、胆汁、血液、玻璃体液和几个脑区。THC在肝组织中消除最快，在6 h内完全消除。THC浓度在脑组织中的下降速度比血液中慢。在脂肪组织中观察到最慢的THC消除，24小时后该分子仍以显著浓度存在。30 min后，不同脑区THC浓度以小脑最高，延髓最低。在肾脏、心脏、脾脏、肌肉和肺中观察到的THC消除动力学与在血液中观察到的那些相当。11-羟基-THC仅在肝脏中发现高水平。在大多数组织中，THC-COOH小于5 ng/g，但胆汁除外，在THC注射后24 h，胆汁中的THC-COOH增加。这项研究证实，即使在一次独特的给药后，THC在大脑中，特别是在脂肪中的长期保留，这可能是重度使用者观察到的不同现象的起源，例如尿液中THC-COOH的长期检测或大麻相关的闪回。此外，这些结果支持了对该动物模型的兴趣，该模型可用于进一步研究大麻素在组织中的分布。(c)2006爱思唯尔爱尔兰有限公司保留所有权利。
This study presents a new animal model, the Large White Pig, which was tested for studying cannabinoids metabolism. The first step has focused on determination of plasma kinetics after injection of Delta(9)-tetrahydrocannabinol (THC) at different dosages. Seven pigs received THC by intravenous injections (50, 100 or 200 mu g/kg). Plasma samples were collected during 48 h. Determination of cannabinoids concentrations were performed by gas chromatography/mass spectrometry. Results showed that plasma kinetics were comparable to those reported in humans. Terminal half-life of elimination was 10.6 h and a volume of distribution of 321/kg was calculated. In a second step, this model was used to determine the kinetic profile of cannabinoids distribution in tissues. Eight Large White male pigs received an injection of THC (200 mu g/kg). Two pigs were sacrificed 30 min after injection, two others after 2, 6 and 24 h. Different tissues were sampled: liver, kidney, heart, lung, spleen, muscle, fat, bile, blood, vitreous humor and several brain areas. The fastest THC elimination was noted in liver tissue, where it was completely eliminated in 6 h. THC concentrations decreased in brain tissue slower than in blood. The slowest THC elimination was observed for fat tissue, where the molecule was still present at significant concentrations 24 h later. After 30 min, THC concentration in different brain areas was highest in the cerebellum and lowest in the medulla oblongata. THC elimination kinetics noted in kidney, heart, spleen, muscle and lung were comparable with those observed in blood. 11-Hydroxy-THC was only found at high levels in liver. THC-COOH was less than 5 ng/g in most tissues, except in bile, where it increased for 24 h following THC injection. This study confirms, even after a unique administration, the prolonged retention of THC in brain and particularly in fat, which could be at the origin of different phenomena observed for heavy users such as prolonged detection of THC-COOH in urine or cannabis-related flashbacks. Moreover, these results support the interest for this animal model, which could be used in further studies of distribution of cannabinoids in tissues. (c) 2006 Elsevier Ireland Ltd. All rights reserved.