目的 建立大鼠血漿及肺部組織中溴己新濃度測定的LC-MS/MS方法，并對大鼠給予鹽酸溴己新霧化吸入溶液受試制劑與參比制劑后藥物在血漿及肺部組織分布進行比較。方法 樣品處理采用簡便的蛋白沉淀法，內標為苯海拉明，采用ZORBAX Eclipse XDB-C₁₈色譜柱，有機相為甲醇，水相為0.5%甲酸-5%甲醇水溶液，采用梯度程序進行洗脫，在電噴霧離子化源（ESI）的正離子模式下以多重反應監(jiān)測（MRM）方式進行檢測。對血漿和肺組織中溴己新的分析方法分別進行了完整驗證和部分驗證。健康SD大鼠隨機分為兩組，分別霧化吸入給予鹽酸溴己新霧化吸入溶液受試及參比制劑，定時采集血漿、肺、氣管支氣管并測定溴己新的濃度。結果 血漿及肺組織中溴己新濃度測定的分析方法驗證各項均符合指導原則規(guī)定。受試制劑與參比制劑在大鼠血漿、肺、氣管支氣管中的分布速度、分布程度基本一致，在主要靶部位氣管支氣管中的相對生物利用度為97.4%。結論 建立的LC-MS/MS分析方法快速、靈敏、簡便，兩種制劑在大鼠血漿及肺部組織分布具有一致性，可為該新劑型的國產化提供數據支持。

Objective To establish an LC-MS/MS method for the determination of bromhexine in rat plasma and lung, and the distribution in plasma and lung tissue was compared between the test and the reference formulations of bromhexine hydrochloride inhalation solution in rats. Methods Samples were pretreated by a simple protein precipitation method with diphenhydramine as the internal standard. Chromatographic separation was performed on a ZORBAX Eclipse XDB-C₁₈ column using a gradient elution program with solvents consisting of methanol and 0.5% formic acid-5% methanol aqueous solution. The detection was operated in the positive ion mode using multiple reaction monitoring (MRM) with an electrospray ionization source (ESI). The analytical methods for plasma and lung tissue were fully and partially validated, respectively. Healthy Sprague-Dawley rats were divided into two groups randomly and administered by inhalation with test and reference formulations of bromhexine hydrochloride inhalation solution, respectively. The plasma, lung and tracheobronchus were collected at predetermined time points and the concentration of bromhexine was measured. Results Bioanalytical method validation results all met the criteria of the guidelines. The distribution rate and extent of bromhexine in plasma, lung and tracheobronchus between the two formulations were consistent. The relative bioavailability in the main target organ tracheobronchus was about 97.4%. Conclusion The LC-MS/MS method established in this study is rapid, sensitive and simple. The distribution of bromhexine between the two formulations in rat plasma and lung tissue is consistent, which can provide data support for the localization of the new formulation.

R969.1

中國醫(yī)學科學院醫(yī)學與健康科技創(chuàng)新工程項目資助（2019-I2M-5-020）