School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, China.
Biomed Chromatogr. 2021 May;35(5):e5066. doi: 10.1002/bmc.5066. Epub 2021 Jan 15.
l-Tetrahydropalmatine (l-THP), an active alkaloid compound isolated from Rhizoma Corydalis-yanhusuo, has been reported to possess biological activity for treating cocaine use. To enhance both oral bioavailability and brain penetration, three formulations of l-THP suspension, mixture of l-THP-puerarin and self-microemulsifying drug delivery systems (SMEDDS) were prepared. A sensitive and reliable ultra-high-performance liquid chromatography with tandem mass spectrometry method was developed and validated for the simultaneous determination of l-THP and its active metabolite l-isocorypalmine (l-ICP) in rat brain. Diazepam was used as the internal standard. The chromatographic separation was achieved on a Bonshell ASB C column at 30°C using acetonitrile-aqueous formic acid as mobile phase in gradient mode. The linearity was validated over the concentration ranges of 4.00-2,500 ng/ml for l-THP and 0.400-500 ng/ml for l-ICP. Full method validation was within the acceptance limits. The method was successfully used to determine the pharmacokinetics of two analytes following oral administration of these three formulations to rats. A significant difference was observed in the main pharmacokinetic parameters between SMEDDS and the suspension, and a 3.25- and 2.97-fold increase in the relative bioavailability of l-THP and l-ICP, respectively, was observed with the SMEDDS compared with the suspension formulation. It was concluded that SMEDDS enhanced the absorption of l-THP and l-ICP and delayed their release in brain.
左旋延胡索乙素（l-THP）是从延胡索中分离得到的一种具有生物活性的生物碱化合物，据报道其具有治疗可卡因使用的作用。为了提高口服生物利用度和脑穿透性，制备了左旋延胡索乙素混悬剂、左旋延胡索乙素-葛根素混合物和自微乳药物传递系统（SMEDDS）三种制剂。建立并验证了一种灵敏、可靠的超高效液相色谱-串联质谱法，用于同时测定大鼠脑组织中的左旋延胡索乙素及其活性代谢物 l-异紫堇定（l-ICP）。地西泮作为内标。在 30°C 下，采用 Bonshell ASB C 柱，以乙腈-水-甲酸为流动相进行梯度洗脱，实现了色谱分离。l-THP 的线性范围为 4.00-2500ng/ml，l-ICP 的线性范围为 0.400-500ng/ml。全方法验证均符合要求。该方法成功用于测定这三种制剂口服给予大鼠后两种分析物的药代动力学。与混悬剂相比，SMEDDS 组的主要药代动力学参数存在显著差异，l-THP 和 l-ICP 的相对生物利用度分别提高了 3.25 倍和 2.97 倍。结果表明，SMEDDS 增强了 l-THP 和 l-ICP 的吸收，并延迟了其在脑内的释放。
