Li Shuping, Teng Liang, Liu Wei, Cheng Xuemei, Jiang Bo, Wang Zhengtao, Wang Chang-Hong
a The MOE Key Laboratory for Standardization of Chinese Medicines, The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine , Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine , Shanghai , China ;
b Department of Pharmacy , The First Affiliated Hospital of Xinjiang Medical University , Urumqi , China ;
Pharm Biol. 2016 Sep;54(9):1768-81. doi: 10.3109/13880209.2015.1127978. Epub 2016 Jan 5.
Context The β-carboline alkaloid harmane is widely distributed in common foods, beverages and hallucinogenic plants. Harmane exerts potential in therapies for Alzheimer's and depression diseases. However, little information on its dynamic metabolic profiles and pharmacokinetics in vivo is currently available. Objective This study investigates the dynamic metabolic profiles and pharmacokinetic properties of harmane and its metabolites in rats in vivo. Materials and methods A highly selective, sensitive and rapid ultra-performance liquid chromatography combined with electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS) method was developed and well-validated for simultaneous quantitative determination of harmane and its uncertain endogenous metabolite harmine, as well as for semiquantitative determination of 10 harmane metabolites in rats after intravenous injection and oral administration of harmane at 1.0 and 30.0 mg/kg, respectively. Results The calibration curves of harmane and harmine showed excellent linearity within the concentration range of 1-2000 ng/mL with acceptable accuracy, precision, selectivity, recovery, matrix effect and stability. Ten metabolites, including harmane but not harmine, were detected and identified after intravenous and oral administration of harmane. The absolute bioavailability of harmane following an oral dose was 19.41 ± 3.97%. According to the AUC0-t values of all the metabolites, the metabolic levels of phase II metabolites were higher than those of phase I metabolites, and the sulphation pathways were the dominant metabolic routes for harmane in both routes of administration. Discussion and conclusion The pharmacokinetic properties of harmane and its 10 metabolites in rats were determined. Sulphate conjugation was the predominant metabolic process of harmane in rats.
β-咔啉生物碱哈尔满广泛分布于常见食物、饮料和致幻植物中。哈尔满在治疗阿尔茨海默病和抑郁症方面具有潜力。然而，目前关于其体内动态代谢谱和药代动力学的信息较少。
本研究调查哈尔满及其代谢产物在大鼠体内的动态代谢谱和药代动力学特性。
建立了一种高选择性、灵敏且快速的超高效液相色谱-电喷雾电离串联质谱联用（UPLC-ESI-MS/MS）方法，并进行了充分验证，用于同时定量测定哈尔满及其不确定的内源性代谢产物去氢骆驼蓬碱，以及分别以1.0和30.0 mg/kg的剂量静脉注射和口服哈尔满后对大鼠体内10种哈尔满代谢产物进行半定量测定。
哈尔满和去氢骆驼蓬碱的校准曲线在1-2000 ng/mL的浓度范围内显示出良好的线性，具有可接受的准确度、精密度、选择性、回收率、基质效应和稳定性。静脉注射和口服哈尔满后，检测并鉴定出10种代谢产物，包括哈尔满但不包括去氢骆驼蓬碱。口服给药后哈尔满的绝对生物利用度为19.41±3.97%。根据所有代谢产物的AUC0-t值，Ⅱ相代谢产物的代谢水平高于Ⅰ相代谢产物，且硫酸化途径是两种给药途径中哈尔满的主要代谢途径。
确定了哈尔满及其10种代谢产物在大鼠体内的药代动力学特性。硫酸结合是大鼠体内哈尔满的主要代谢过程。
