Kong Wai Mun, Chik Zamri, Mohamed Zahurin, Alshawsh Mohammed A
Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
University of Malaya Bioequivalence and Testing Centre (UBAT), Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia.
Comb Chem High Throughput Screen. 2017;20(9):796-803. doi: 10.2174/1386207320666171026121820.
Mitragynine, a major active alkaloid of Mitragyna speciosa, acts as an agonist on µ-opioid receptors, producing effects similar to morphine and other opioids. It has been traditionally utilized to alleviate opiate withdrawal symptoms. Besides consideration about potency and selectivity, a good drug must possess a suitable pharmacokinetic profile, with suitable absorption, distribution, metabolism, excretion and toxicity (ADME-Tox) profile, in order to have a high chance of success in clinical trials.
The purity of mitragynine in a Mitragyna speciosa alkaloid extract (MSAE) was determined using Ultra-Fast Liquid Chromatography (UFLC). In vitro high throughput ADMETox studies such as aqueous solubility, plasma protein binding, metabolic stability, permeability and cytotoxicity tests were carried out to analyze the physicochemical properties of MSAE and mitragynine. The UFLC quantification revealed that the purity of mitragynine in the MSAE was 40.9%.
MSAE and mitragynine are highly soluble in aqueous solution at pH 4.0 but less soluble at pH 7.4. A parallel artificial membrane permeability assay demonstrated that it is extensively absorbed through the semi-permeable membrane at pH 7.4 but very poorly at pH 4.0. Both are relatively highly bound to plasma proteins (> 85 % bound) and are metabolically stable to liver microsomes (> 84 % remained unchanged). In comparison to MSAE, mitragynine showed higher cytotoxicity against WRL 68, HepG2 and Clone 9 hepatocytes after 72 h treatment.
The obtained ADME and cytotoxicity data demonstrated that both MSAE and mitragynine have poor bioavailability and have the potential to be significantly cytotoxic.
帽柱木碱是帽柱木属植物的一种主要活性生物碱，作为μ-阿片受体激动剂，其作用类似于吗啡和其他阿片类药物。传统上它被用于缓解阿片类药物戒断症状。除了考虑效力和选择性外，一种好的药物必须具有合适的药代动力学特征，即具有合适的吸收、分布、代谢、排泄和毒性（ADME-Tox）特征，以便在临床试验中有较高的成功几率。
使用超快速液相色谱（UFLC）测定帽柱木属植物生物碱提取物（MSAE）中帽柱木碱的纯度。进行了体外高通量ADMETox研究，如水溶性、血浆蛋白结合、代谢稳定性、渗透性和细胞毒性测试，以分析MSAE和帽柱木碱的物理化学性质。UFLC定量分析显示，MSAE中帽柱木碱的纯度为40.9%。
MSAE和帽柱木碱在pH 4.0的水溶液中高度可溶，但在pH 7.4时溶解度较低。平行人工膜通透性试验表明，它在pH 7.4时可通过半透膜大量吸收，但在pH 4.0时吸收很差。两者都相对高度结合血浆蛋白（>85%结合），并且对肝微粒体代谢稳定（>84%保持不变）。与MSAE相比，帽柱木碱在处理72小时后对WRL 68、HepG2和Clone 9肝细胞显示出更高的细胞毒性。
获得的ADME和细胞毒性数据表明，MSAE和帽柱木碱的生物利用度都很差，并且有显著的细胞毒性潜力。
