Jeon Ji-Hyeon, Jeon So-Yeon, Baek Yeon-Ju, Park Chan-E, Choi Min-Koo, Han Young Taek, Song Im-Sook
BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, Vessel-Organ Interaction Research Center (VOICE), College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea.
College of Pharmacy, Dankook University, Cheon-an 31116, Republic of Korea.
Pharmaceutics. 2024 Jul 12;16(7):934. doi: 10.3390/pharmaceutics16070934.
The quinoline alkaloid 2-(quinoline-8-carboxamido)benzoic acid (2-QBA), which is isolated from sp. SCSIO06786, a deep sea-derived fungus, has been suggested as a therapeutic candidate for the treatment of Parkinson's disease. We developed an analytical method for 2-QBA using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) in mouse plasma, in which a protein precipitation method for the sample preparation of 2-QBA in mouse plasma was used due to its simplicity and good extraction recovery rates (80.49-97.56%). The linearity of the calibration standard sample, inter- and intraday precision and accuracy, and stability of three quality control samples were suitable based on the assessment criteria and the lower limit of quantification (LLOQ) of the 2-QBA was 1 ng/mL. A pharmacokinetic study of 2-QBA was performed in mice divided into oral (2.0, 5.0, and 15 mg/kg) and intravenous (0.5 and 1.0 mg/kg) administration groups. The absolute oral bioavailability (BA) range of 2-QBA was calculated as 68.3-83.7%. Secondary peaks were observed at approximately 4-8 h after the oral administration of 2-QBA at all doses. The elimination half-life of the orally administered 2-QBA was significantly longer than that of the intravenous 2-QBA. In addition, glucuronide metabolites of 2-QBA were identified. They were transformed into 2-QBA using the β-glucuronidase treatment. Furthermore, the 2-QBA was readily absorbed from the jejunum to lower ileum. Taken together, the secondary peaks could be explained by the enterohepatic circulation of 2-QBA. In conclusion, the reabsorption of orally administered 2-QBA could contribute to the high oral BA of 2-QBA and could be beneficial for the efficacy of 2-QBA. Moreover, the simple and validated analytical method for 2-QBA using LC-MS/MS was applied to the pharmacokinetic study and BA assessments of 2-QBA in mice and would be helpful for subsequent pharmacokinetic studies, as well as for evaluations of the toxicokinetics and pharmacokinetic-pharmacodynamic correlation of 2-QBA to assess its potential as a drug.
从深海来源的真菌 sp. SCSIO06786 中分离得到的喹啉生物碱 2-(喹啉-8-甲酰胺基)苯甲酸(2-QBA)，已被认为是治疗帕金森病的候选药物。我们开发了一种在小鼠血浆中使用液相色谱-串联质谱(LC-MS/MS)分析 2-QBA 的方法，其中采用蛋白质沉淀法制备小鼠血浆中的 2-QBA，因其操作简单且提取回收率良好(80.49%-97.56%)。根据评估标准，校准标准样品的线性、日内和日间精密度与准确度以及三个质量控制样品的稳定性均合适，2-QBA 的定量下限(LLOQ)为 1 ng/mL。对分为口服(2.0、5.0 和 15 mg/kg)和静脉注射(0.5 和 1.0 mg/kg)给药组的小鼠进行了 2-QBA 的药代动力学研究。2-QBA 的绝对口服生物利用度(BA)范围计算为 68.3%-83.7%。在所有剂量口服 2-QBA 后约 4-8 小时观察到二次峰。口服 2-QBA 的消除半衰期明显长于静脉注射 2-QBA 的消除半衰期。此外，还鉴定出了 2-QBA 的葡萄糖醛酸代谢物。使用β-葡萄糖醛酸酶处理将它们转化为 2-QBA。此外，2-QBA 很容易从空肠吸收到回肠末端。综上所述，二次峰可以用 2-QBA 的肠肝循环来解释。总之，口服 2-QBA 的重吸收可能有助于 2-QBA 的高口服 BA，并可能有利于 2-QBA 的疗效。此外，使用 LC-MS/MS 的简单且经过验证的 2-QBA 分析方法应用于小鼠 2-QBA 的药代动力学研究和 BA 评估，将有助于后续的药代动力学研究，以及评估 2-QBA 的毒代动力学和药代动力学-药效学相关性，以评估其作为药物的潜力。
