利用MMDL评价尼麦角林胶囊人体生物利用度

Study on Relative Bioavailability of Nicergoline Capsules in Healthy Volunteers by the Determination of MMDL

目的建立测定人血浆中1-甲基-10α-甲氧基-9,10-二氢麦角醇(MMDL)浓度的高效液相色谱法,并以MMDL体内的水平为指标研究尼麦角林胶囊的人体生物利用度。方法以二氯甲烷-异丙醇(9∶1)为萃取液,美索巴莫为内标,血浆样品经液-液萃取浓缩后,经Diamonsil C18柱分离,以乙腈-20 mmol·L-1磷酸二氢钾溶液(22∶78)为流动相,在225 nm波长处检测。18名健康男性志愿者采用随机交叉给药方案,分别单剂量po60 mg受试制剂或参比制剂,不同时间点采血,用HPLC测定血浆中MMDL,比较二者生物利用度。结果MMDL和内标分离良好,内源性杂质不干扰测定,在浓度为1.7～207μg·L-1内,MMDL浓度与峰面积比线性关系良好,方法回收率为91.7%～101.8%,日内、日间RSD分别小于9.7%(n=5)、11.6%(n=15)。单剂量po受试制剂或参比制剂60 mg后,MMDL的ρmax分别为(97.9±54.6)和(103.0±60.5)μg·L-1;tmax分别为(1.2±0.4)和(1.2±0.4)h;t1/2分别为(3.7±2.6)和(4.4±3.0)h;AUC0→12 h分别为(283.7±218.4)和(305.3±244.6)μg·h·L-1。相对生物利用度为(93.8±6.4)%。结论此方法灵敏、简便、准确度高,可用于尼麦角林体内过程研究。国产尼麦角林和国外产品的体内过程无显著性差别,两者为生物等效性制剂。

OBJECTIVE To establish a HPLC method for the determination of MMDL （1-methyl-10cc-methoxy-9, 10- dihydrolysergol） in plasma and study the relative bioavailability of domestic and imported nicergoline capsules. METHODS MMDL were extracted from plasma sample with dichloromethane （including 10% isopropanol） and separated on a Diamonsil C18 column（4.6 mm × 200 mm, 5 μm）. The mobile phase consisted of acetonitrile -20 mmol · L^-1 potassium dihydrogen phosphate （22： 78）, the flow rate was 1 mL · min ^-1 , and methoearbamol was used as the internal standard. A single dose of 60 mg of domestic or imported capsules was given to 18 healthy volunteers in a randomized crossover study. MMDL concentrations in plasma was determined by the developed HPLC method, and then the pharmacokinetics and bioavailability were studied. RESULTS MMDL was separated well from other metabolites and endogenous substance, the standard curve was linear （r = 0. 999 7） within the range of 1.7 to 207 μg · L^-1 for MMDL. The main parameters for MMDL were as follows ： pax （97.9 ± 54. 6） and （ 103.0 ± 60. 5 ） μg · L^-1, tmax （ 1.2 ± 0. 4） and （ 1.2 ± 0.4 ） h, t1/2 （ 3.7 ± 2.6 ） and （ 4.0 ± 3.0 ） b, AUC0-42 h, （ 283.7 ± 218.4 ） and （ 305.3 ± 244.6 ） μg ·h· L^-1 respectively. The relative bioavailability of domestic to imported capsules was （93.8 ± 6. 4） %. CONCLUSION The established HPLC method was accuracy and sensitive for assay of plasma MMDL concentration. And the concentrations of MMDL in plasma were suitable for the bioavailability evaluation of nicergotine capsules. The results of statistics showed there were no significant differences between two preparations, and bioequivatence was observed.