Limpanuparb Taweetham, Noorat Rattha, Tantirungrotechai Yuthana
Science Division, Mahidol University International College, Mahidol University, Nakhon Pathom, 73170, Thailand.
Division of Chemistry, Faculty of Science and Technology, Thammasat University, Pathum Thani, 12120, Thailand.
BMC Res Notes. 2019 Jul 22;12(1):451. doi: 10.1186/s13104-019-4461-3.
Mitragynine is the main active compound of Mitragyna speciose (Kratom in Thai). The understanding of mitragynine derivative metabolism in human body is required to develop effective detection techniques in case of drug abuse or establish an appropriate dosage in case of medicinal uses. This in silico study is based upon in vivo results in rat and human by Philipp et al. (J Mass Spectrom 44:1249-1261, 2009).
Gas-phase structures of mitragynine, 7-hydroxymitragynine and their metabolites were obtained by quantum chemical method at B3LYP/6-311++G(d,p) level. Results in terms of standard Gibbs energies of reaction for all metabolic pathways are reported with solvation energy from SMD model. We found that 7-hydroxy substitution leads to changes in reactivity in comparison to mitragynine: position 17 is more reactive towards demethylation and conjugation with glucuronic acid and position 9 is less reactive towards conjugation with glucuronic acid. Despite the changes, position 9 is the most reactive for demethylation and position 17 is the most reactive for conjugation with glucuronic acid for both mitragynine and 7-hydroxymitragynine. Our results suggest that 7-hydroxy substitution could lead to different metabolic pathways and raise an important question for further experimental studies of this more potent derivative.
帽柱木碱是帽柱木（泰国 kratom）的主要活性化合物。为了在药物滥用情况下开发有效的检测技术或在药用情况下确定合适的剂量，需要了解帽柱木碱衍生物在人体内的代谢情况。这项计算机模拟研究基于菲利普等人（《质谱学报》44:1249 - 1261，2009年）在大鼠和人体上的体内实验结果。
采用量子化学方法在B3LYP/6 - 311++G(d,p)水平获得了帽柱木碱、7 - 羟基帽柱木碱及其代谢产物的气相结构。报告了所有代谢途径的反应标准吉布斯自由能结果，并包含来自SMD模型的溶剂化能。我们发现，与帽柱木碱相比，7 - 羟基取代导致反应性发生变化：17位对去甲基化和与葡萄糖醛酸结合的反应性更高，9位对与葡萄糖醛酸结合的反应性更低。尽管有这些变化，但对于帽柱木碱和7 - 羟基帽柱木碱来说，9位对去甲基化的反应性最高，17位对与葡萄糖醛酸结合的反应性最高。我们的结果表明，7 - 羟基取代可能导致不同的代谢途径，并为进一步研究这种更有效的衍生物提出了一个重要的实验问题。
