Abduraman Muhammad Asyraf, Amanah Azimah, Hamid Shahrul Bariyah Sahul, Abdullah Mohammad Farris Iman Leong, Sulaiman Shaida Fariza, Tan Mei Lan
Advanced Medical and Dental Institute, Universiti Sains Malaysia, 13200, Kepala Batas, Pulau Pinang, Malaysia.
Malaysian Institute of Pharmaceuticals and Nutraceuticals, National Institute of Biotechnology Malaysia, 11700, Gelugor, Pulau Pinang, Malaysia.
J Pharm Pharmacol. 2025 Feb 3;77(2):321-334. doi: 10.1093/jpp/rgae131.
Kratom preparation containing Mitragyna speciosa Korth plant is frequently used as a recreational drug. Mitragynine, a major alkaloid isolated from M. speciosa, is often detected concurrently with other drugs during forensic analysis, indicating a safety concern. P-glycoprotein (P-gp) is a multidrug transporter. Modulation of P-gp transport activity by drugs or herbal compounds in the brain may lead to drug-herb interactions, resulting in neurotoxicity. We aim to determine the effects of mitragynine on the P-gp regulation and possible neurotoxicity.
The effects of mitragynine on the P-gp regulation were investigated in human brain capillary endothelial cells (hCMEC/D3) using molecular docking and dynamic simulation and an optimized bidirectional transport assay, respectively. Repeated-dose treatment and neurotoxicity assessment were carried out using a blood-brain barrier model and polimerase chain reaction (PCR) array.
Mitragynine inhibits the P-gp transport activity via binding onto the nucleotide-binding domain site and forms a stable interaction with the P-gp protein complex. Nontoxic concentrations of mitragynine (<4 μM) and substrate drugs (0.001 μM) in the cells significantly enhanced endothelial cell permeability and elicited signs of neurotoxicity in PC-12 cells.
Mitragynine is likely a P-gp inhibitor, hence concurrent administration of kratom products with P-gp substrates may lead to clinically significant interactions and neurotoxicity.
含有帽柱木属植物的 kratom 制剂常被用作消遣性药物。在法医分析中，从帽柱木中分离出的主要生物碱帽柱木碱，经常与其他药物同时被检测到，这表明存在安全隐患。P-糖蛋白（P-gp）是一种多药转运蛋白。大脑中药物或草药化合物对 P-gp 转运活性的调节可能导致药物-草药相互作用，从而产生神经毒性。我们旨在确定帽柱木碱对 P-gp 调节的影响以及可能的神经毒性。
分别使用分子对接和动态模拟以及优化的双向转运试验，在人脑微血管内皮细胞（hCMEC/D3）中研究帽柱木碱对 P-gp 调节的影响。使用血脑屏障模型和聚合酶链反应（PCR）阵列进行重复给药治疗和神经毒性评估。
帽柱木碱通过结合到核苷酸结合结构域位点抑制 P-gp 转运活性，并与 P-gp 蛋白复合物形成稳定的相互作用。细胞中无毒浓度的帽柱木碱（<4 μM）和底物药物（0.001 μM）显著增强了内皮细胞通透性，并在 PC-12 细胞中引发了神经毒性迹象。
帽柱木碱可能是一种 P-gp 抑制剂，因此 kratom 产品与 P-gp 底物同时给药可能导致具有临床意义的相互作用和神经毒性。
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