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马钱子碱及其纳米结构脂质载体在大鼠体内的药动学比较研究
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| 篇名： | 马钱子碱及其纳米结构脂质载体在大鼠体内的药动学比较研究 |
| TITLE： | |
| 摘要： | 目的：建立测定大鼠血浆中马钱子碱质量浓度的方法，并比较马钱子碱及其纳米结构脂质载体（NLC）在大鼠体内的药动学差异。方法：16只雄性SD大鼠随机分为马钱子碱NLC溶液组和马钱子碱溶液组（均以生理盐水为溶剂，质量浓度均为1.28 mg/mL），每组8只。所有大鼠均于尾静脉单次注射相应药物溶液（10 mg/kg），分别于给药前及给药后15、20、30、40、45、60、90、120、150、180、210、240、480 min自眼底静脉丛毛细血管取血0.5 mL，采用高效液相色谱法（HPLC）测定。色谱柱为Dikma C18，流动相为甲醇-含乙酸和三乙胺的混合水溶液（30 ∶ 70，V/V），检测波长为265 nm，流速为1 mL/min，柱温为30 ℃，进样量为10 μL。采用DAS 2.0软件计算两组大鼠的药动学参数，采用F检验考察两者的差异。结果：马钱子碱血药浓度的线性范围为1.03～66.00 μg/mL（R2＝0.999 6），定量下限为1.03 μg/mL，最低检测限为0.515 μg/mL；日内、日间RSD＜5％；方法回收率为84.90％～100.88％、提取回收率为80.60％～91.98％（RSD均小于10％）。大鼠尾静脉单次注射马钱子碱NLC溶液与马钱子碱溶液后的平均药-时曲线均符合二室模型，吸收半衰期（t1/2α）分别为（0.24±0.11）、（0.06±0.03）h，消除半衰期（t1/2β）分别为（2.90±0.22）、（0.57±0.32）h，药-时曲线下面积（AUC0-t）分别为（88.00±6.98）、（28.50±5.87）μg·h/mL，AUC0-∞分别为（109.96±7.99）、（45.06±6.66）μg·h/mL。与马钱子碱溶液组比较，马钱子碱NLC溶液组大鼠的tl/2α、t1/2β、AUC0-t、AUC0-∞均显著增加，清除率、药物从中央室消除的一级速率常数、药物从中央室向周边室转运的一级速率常数均显著降低（P＜0.05或P＜0.01）；而两组大鼠药物从周边室向中央室转运的一级速率常数比较，差异无统计学意义（P＞0.05）。结论：本研究建立的HPLC法操作简便，专属性强，灵敏度、精密度及回收率高，可用于大鼠血浆中马钱子碱质量浓度的测定及药动学的研究。将马钱子碱制成NLC后，其药动学参数变化明显，药物在体内的滞留时间显著延长，清除率显著降低。 |
| ABSTRACT： | OBJECTIVE： To establish a method for the determination of brucine concentration in plasma of rats， and to compare the pharmacokinetic differences between brucine and its nanostructure lipid carrier （NLC） in rats. METHODS： Sixteen male SD rats were randomly divided into brucine NLC solution group and brucine solution group （using normal saline as solvent， and containing brucine 1.28 mg/mL）， with 8 rats in each group. They were given relevant solution 10 mg/kg via tail vein. Blood sample 0.5 mL was collected from fundus venous plexus capillary before medication and 15， 20， 30， 40， 45， 60， 90， 120， 150， 180， 210， 240， 480 min after medication. HPLC method was adopted. The determination was performed on Dikma C18 column with mobile phase consisted of methanol-water containing acetic acid and triethylamine （30 ∶ 70，V/V） at the flow rate of 1 mL/min. The detection wavelength was set at 265 nm， and column temperature was 30 ℃. Sample size was 10 μL. Pharmacokinetic parameters of rats in 2 groups were calculated by using DAS 2.0 software， and the difference of them were compared by F test. RESULTS： The linear range of brucine plasma concentration were 1.03-66.00 μg/mL （R2＝0.999 6）； the limit of quantitation was 1.03 μg/mL， and lowest detection limit was 0.515 μg/mL. RSDs of intra-day and inter-day were lower than 5％； method recoveries were 84.90％-100.88％， extraction recoveries were 80.60％-91.98％（all RSDs were lower than 10％）. Average plasma concentration-time curve of single administration of brucine NLC solution and brucine solution were all in line with two-compartment model after medication via tail vein. The pharmacokinetic parameters included t1/2α were （0.24±0.11） and（0.06±0.03）h； t1/2β were （2.90±0.22） and （0.57±0.32）h； AUC0-t were （88.00±6.98） and （28.50±5.87）μg·h/mL； AUC0-∞ were（109.96±7.99） and （45.06±6.66）μg·h/mL. Compared with brucine solution group， t1/2α， t1/2β， AUC0-t and AUC0-∞ of brucine NLC solution group were increased significantly； while CL， k10 and k12 were decreased significantly， with statistical significance （P＜0.05 or P＜0.01）. There was no statistical significance in k21 between 2 groups （P＞0.05）. CONCLUSIONS： Established HPLC method is simple， specific， sensitive， precise and highly recoverable. It can be used for the determination of plasma concentration and phamacokinetic study of brucine in rats. After brucine NLC is prepared， the pharmacokinetic parameters of brucine change significantly； retention time of brucine is significantly prolonged and the clearance rate decreases significantly. |
| 期刊： | 2018年第29卷第20期 |
| 作者： | 管庆霞，张悦，邹淑君，孙爽，李云行，华晓丹，杨志欣，李秀岩，王艳宏 |
| AUTHORS： | GUAN Qingxia，ZHANG Yue，ZOU Shujun，SUN Shuang，LI Yunxing，HUA Xiaodan，YANG Zhixin，LI Xiuyan，WANG Yanhong |
| 关键字： | 马钱子碱；纳米结构脂质载体；高效液相色谱法；血药浓度；药动学；大鼠；比较研究 |
| KEYWORDS： | Brucine； Nanostructure liquid carrier； HPLC； Plasma concentration； Pharmacokinetics； Rat； Comparative study |
| 阅读数： | 298 次 |
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