7-羟基帽柱木碱（帽柱木碱的一种活性代谢产物）在斯普拉格-道利大鼠体内和体外的药代动力学特征
In Vitro and In Vivo Pharmacokinetic Characterization of 7-Hydroxymitragynine, an Active Metabolite of Mitragynine, in Sprague-Dawley Rats.
作者信息
Chiang Yi-Hua, Kanumuri Siva Rama Raju, Kuntz Michelle A, Senetra Alexandria S, Berthold Erin C, Kamble Shyam H, Mukhopadhyay Sushobhan, Hampson Aidan J, McCurdy Christopher R, Sharma Abhisheak
机构信息
Department of Pharmaceutics, College of Pharmacy, University of Florida, 1345 Center Drive Medical Sciences Building MSB P3-20B, Gainesville, FL, 32610, USA.
Translational Drug Development Core, Clinical and Translational Science Institute, University of Florida, Gainesville, FL, USA.
出版信息
Eur J Drug Metab Pharmacokinet. 2025 May;50(3):205-218. doi: 10.1007/s13318-025-00939-2. Epub 2025 Mar 22.
BACKGROUND AND OBJECTIVES
Kratom, a Southeast Asian tree, has been researched for its potential as a therapeutic for substance use disorders. The most abundant alkaloid in kratom, mitragynine, is being investigated individually for opioid use disorder. However, the active metabolite of mitragynine,7-hydroxymitragynine (7-HMG) has raised concerns because of its high binding affinity to μ-opioid receptors and abuse potential. This study examines various pharmacokinetic parameters of 7-HMG in both in vitro and in vivo models.
METHODS
In vitro pharmacokinetic properties were investigated using human colorectal adenocarcinoma cell monolayers (Caco-2 cells), rat plasma, rat liver microsomes, and rat hepatocytes to determine the permeability, plasma protein binding, and microsomal and hepatocyte stability of 7-HMG, respectively. Oral and intravenous (IV) pharmacokinetic studies of 7-HMG were performed in male Sprague-Dawley rats.
RESULTS
7-HMG exhibits high permeability across Caco-2 cells (19.7 ± 1.0 × 10 cm/s), with a relatively low plasma protein binding of 73.1 ± 0.6% to mitragynine. The hepatic extraction ratio was 0.3 and 0.6 in rat liver microsomes and hepatocytes, respectively, indicating that 7-HMG is an intermediate hepatic extraction compound. Oral and IV pharmacokinetic studies were performed in male rats. The volume of distribution was 2.7 ± 0.4 l/kg and the clearance was 4.0 ± 0.3 l/h/kg after IV administration. After oral dosing (5 mg/kg), a C of 28.5 ± 5.0 ng/ml and T of 0.3 ± 0.1 h were observed. However, the oral bioavailability of 7-HMG was only 2.7 ± 0.3%. The results demonstrate 7-HMG is rapidly absorbed but has low oral bioavailability. Mitragynine pseudoindoxyl (MGPI) is a metabolite of 7-HMG that is a more potent µ-opioid agonist than 7-HMG. The parent-to-metabolite ratio for MGPI following IV 7-HMG administration was 0.5 ± 0.1%, indicating very limited systemic exposure to MGPI.
CONCLUSIONS
This study reports the pharmacokinetic parameters of 7-HMG to help with the development of mitragynine, as a therapeutic.
背景与目的
kratom是一种东南亚树木，其作为物质使用障碍治疗药物的潜力已得到研究。kratom中含量最丰富的生物碱——帽柱木碱，正被单独研究用于阿片类物质使用障碍。然而，帽柱木碱的活性代谢产物7-羟基帽柱木碱（7-HMG）因其对μ-阿片受体的高结合亲和力和滥用潜力而引发关注。本研究在体外和体内模型中研究了7-HMG的各种药代动力学参数。
方法
使用人结肠腺癌单层细胞（Caco-2细胞）、大鼠血浆、大鼠肝微粒体和大鼠肝细胞分别研究7-HMG的体外药代动力学特性，以确定其通透性、血浆蛋白结合率以及微粒体和肝细胞稳定性。对雄性斯普拉格-道利大鼠进行了7-HMG的口服和静脉药代动力学研究。
结果
7-HMG在Caco-2细胞上表现出高通透性（19.7±1.0×10 cm/s），与帽柱木碱相比，其血浆蛋白结合率相对较低，为73.1±0.6%。在大鼠肝微粒体和肝细胞中的肝提取率分别为0.3和0.6，表明7-HMG是一种中等肝提取化合物。对雄性大鼠进行了口服和静脉药代动力学研究。静脉给药后，分布容积为2.7±0.4 l/kg，清除率为4.0±0.3 l/h/kg。口服给药（5 mg/kg）后，观察到C为28.5±5.0 ng/ml，T为0.3±0.1 h。然而，7-HMG的口服生物利用度仅为2.7±0.3%。结果表明7-HMG吸收迅速，但口服生物利用度低。帽柱木碱假吲哚酚（MGPI）是7-HMG的一种代谢产物，它是一种比7-HMG更强效的μ-阿片激动剂。静脉注射7-HMG后，MGPI的母体与代谢产物比率为0.5±0.1%，表明MGPI的全身暴露非常有限。
结论
本研究报告了7-HMG的药代动力学参数，以帮助开发作为治疗药物的帽柱木碱。
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