The quinoline alkaloid 2-(quinoline-8-carboxamido)benzoic acid (2-QBA), which is isolated from Aspergillus 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.

中文翻译：

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2-(喹啉-8-甲酰胺基)苯甲酸 (2-QBA) 在小鼠体内的药代动力学和肠肝循环


喹啉生物碱 2-(喹啉-8-甲酰胺基)苯甲酸 (2-QBA)，从曲霉属物种中分离出来。 SCSIO06786 是一种深海来源的真菌，已被建议作为治疗帕金森病的候选药物。我们开发了一种使用液相色谱-串联质谱 (LC-MS/MS) 分析小鼠血浆中 2-QBA 的方法，其中使用蛋白质沉淀法来制备小鼠血浆中 2-QBA 的样品，因为该方法具有以下优点：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度、日间和日内精密度和准确度以及稳定性均合适，2-QBA 的定量下限 (LLOQ) 为 1 ng/mL。 2-QBA 的药代动力学研究在小鼠中进行，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。 2-QBA 的绝对口服生物利用度 (BA) 范围计算为 68.3-83.7%。口服所有剂量的 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。此外，还鉴定了 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下部。综合起来，次要峰可以通过 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，并且可能有利于2-QBA的功效。 此外，利用LC-MS/MS对2-QBA进行简单且经过验证的分析方法，应用于小鼠体内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毒代动力学的评估和 2-QBA 的药代动力学-药效学相关性，以评估其作为药物的潜力。