School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China.
School of Environmental and Chemical Engineering, Zhaoqing University, Zhaoqing 526061, China.
Molecules. 2019 Jan 14;24(2):283. doi: 10.3390/molecules24020283.
10-Dehydroxyl-12-demethoxy-conophylline is a natural anticancer candidate. The motivation of this study was to explore the pharmacokinetic profiles, tissue distribution, and plasma protein binding of 10-dehydroxyl-12-demethoxy-conophylline in Sprague Dawley rats. A rapid, sensitive, and specific ultra-performance liquid chromatography (UPLC) system with a fluorescence (FLR) detection method was developed for the determination of 10-dehydroxyl-12-demethoxy-conophylline in different rat biological samples. After intravenous (i.v.) dosing of 10-dehydroxyl-12-demethoxy-conophylline at different levels (4, 8, and 12 mg/kg), the half-life t of intravenous administration was about 7 min and the t was about 68 min. The AUC increased in a dose-proportional manner from 68.478 μg/L·min for 4 mg/kg to 305.616 mg/L·min for 12 mg/kg. After intragastrical (.) dosing of 20 mg/kg, plasma levels of 10-dehydroxyl-12-demethoxy-conophylline peaked at about 90 min. 10-dehydroxyl-12-demethoxy-conophyllinea absolute oral bioavailability was only 15.79%. The pharmacokinetics process of the drug was fit to a two-room model. Following a single i.v. dose (8 mg/kg), 10-dehydroxyl-12-demethoxy-conophylline was detected in all examined tissues with the highest in kidney, liver, and lung. Equilibrium dialysis was used to evaluate plasma protein binding of 10-dehydroxyl-12-demethoxy-conophylline at three concentrations (1.00, 2.50, and 5.00 µg/mL). Results indicated a very high protein binding degree (over 80%), reducing substantially the free fraction of the compound.
10-去羟基-12-去甲氧基-可待因碱是一种天然的抗癌候选药物。本研究的目的是探索 10-去羟基-12-去甲氧基-可待因碱在 Sprague Dawley 大鼠体内的药代动力学特征、组织分布和血浆蛋白结合情况。建立了一种快速、灵敏、专属性强的超高效液相色谱（UPLC）-荧光（FLR）检测法，用于测定不同大鼠生物样品中的 10-去羟基-12-去甲氧基-可待因碱。静脉注射（i.v.）不同剂量（4、8 和 12 mg/kg）的 10-去羟基-12-去甲氧基-可待因碱后，其静脉给药半衰期 t 约为 7 min， t 约为 68 min。AUC 以剂量比例的方式从 4 mg/kg 的 68.478μg/L·min 增加到 12 mg/kg 的 305.616μg/L·min。灌胃给予 20 mg/kg 后，10-去羟基-12-去甲氧基-可待因碱的血浆水平在约 90 min 时达到峰值。10-去羟基-12-去甲氧基-可待因碱的绝对口服生物利用度仅为 15.79%。该药物的药代动力学过程符合二室模型。单次静脉注射（8 mg/kg）后，在所有检测的组织中均可检测到 10-去羟基-12-去甲氧基-可待因碱，其在肾脏、肝脏和肺中的含量最高。平衡透析法用于评价 10-去羟基-12-去甲氧基-可待因碱在三个浓度（1.00、2.50 和 5.00μg/mL）下的血浆蛋白结合率。结果表明，该化合物具有非常高的蛋白结合度（超过 80%），大大降低了其游离分数。
