芪葵缓释片中6种活性成分在兔血浆中的药动学研究

目的以芪葵颗粒为参照,比较芪葵缓释片中6种成分在兔血浆内的药动学行为差异。方法以地西泮作为内标建立兔血浆中黄芪甲苷、金丝桃苷、异槲皮苷、芦丁、莫诺苷、马钱苷的LC-MS/MS检测方法。考察兔ig给予芪葵缓释片及芪葵颗粒后不同时间的血药浓度变化,并计算6种成分的药动学参数。结果 6种有效成分线性回归方程分别为黄芪甲苷Y=1.0×10~(-4) X-0.009 9(r=0.999 7);莫诺苷Y=1.0×10~(-4) X+0.038 7(r=0.999 4)、马钱苷Y=3.0×10~(-5) X+0.008 7(r=0.999 3)、金丝桃苷Y=1.0×10~(-3) X-0.016 1(r=0.999 0)、芦丁Y=5.0×10~(-4) X-0.011 5(r=0.999 4)、异槲皮苷Y=1.7×10~(-3) X-0.307 5(r=0.999 2);日内、日间精密度和准确度以及提取回收率均符合要求。兔ig给予芪葵缓释片及芪葵颗粒后,芪葵颗粒中莫诺苷、马钱苷、黄芪甲苷、芦丁、金丝桃苷、异槲皮苷达峰浓度(C_(max))分别为(1.333±0.051)、(1.238±0.164)、(0.830±0.079)、(0.127±0.017)、(0.444±0.048)、(0.223±0.048)mg/L;t1/2分别为(3.848±0.311)、(3.822±0.757)、(4.982±1.140)、(3.730±0.298)、(4.732±0.642)、(5.132±0.901)h;AUC_(0～t)分别为(3.069±0.307)、(2.891±0.943)、(2.079±0.306)、(0.313±0.068)、(1.087±0.177)、(0.496±0.129)mg·h/L。芪葵缓释片中莫诺苷、马钱苷、黄芪甲苷、芦丁、金丝桃苷、异槲皮苷的C_(max)分别为(0.985±0.130)、(0.961±0.175)、(0.693±0.101)、(0.094±0.012)、(0.354±0.045)、(0.201±0.037)mg/L;t1/2分别为(4.691±0.337)、(5.62±1.640)、(6.408±0.707)、(4.103±0.341)、(6.048±0.882)、(5.803±0.590)h;AUC_(0～t)分别为(5.191±1.046)、(6.168±1.250)、(4.293±0.823)、(0.485±0.103)、(1.840±0.432)、(0.924±0.190)mg·h/L。芪葵缓释片与芪葵颗粒相比,莫诺苷、马钱苷、黄芪甲苷、芦丁、金丝桃苷、异槲皮苷相对生物利用度分别为169.1%、213.3%、206.5%、156.0%、169.3%、186.3%。结论芪葵缓释片能显著提高各有效成分的生物利用度。

Pharmacokinetic study on six active ingredients of Qikui Sustained-release Tablets in rabbit plasma

Objective To compare the differences in pharmacokinetic behavior of six ingredients in Qikui Sustained-release Tablets in rabbit plasma. Qikui Granules was taken as reference. Methods Diazepam was used as internal standard. LC-MS/MS detection methods of astragaloside, hyperin, isoquercitrin, rutin, morroniside, and loganin in rabbit plasma were established, and pharmacokinetic parameters of six components were calculated. Results Six active ingredients'' equation of linear regressions were:astragaloside Y=1.0×10^-4 X-0.009 9 (r=0.999 7), morroniside Y=1.0×10^-4 X + 0.038 7 (r=0.999 4), loganin Y=3.0×10^-5 X + 0.008 7 (r=0.999 3), hyperin Y=1.0×10^-3 X-0.016 1 (r=0.999 0), rutin Y=5.0×10^-4 X-0.011 5 (r=0.999 4), isoquercitrin Y=1.7×10^-3X-0.307 5(r=0.999 2). Intra-day and inter-day precision and accuracy and recovery rate were up to the mustard. After Qikui Sustained-release Tablets and Qikui Granules being given by gavege, the maximal concentration (C_max) of morroniside, loganin, astragaloside, rutin, hyperin, and isoquerctirin in Qikui Granules were (1.333 ±0.051), (1.238 ±0.164), (0.83 ±0.079), (0.127 ±0.017),(0.444 ±0.048), and (0.223 ±0.048) mg/L, t_1/2 were (3.848 ±0.311), (3.822 ±0.757), (4.982 ±1.14), (3.73 ±0.298), (4.732 ±0.642), and (5.132 ±0.901) h, respectively, AUC_(0-t) were (3.069 ±0.307), (2.891 ±0.943), (2.079 ±0.306), (0.313 ±0.068), (1.087 ±0.177), (0.496 ±0.129) mg·h/L, respectively, C_max of morroniside, loganin, astragaloside, rutin, hyperin, and isoquerctirin in Qikui Sustained-release Tablets were (0.985 ±0.13), (0.961 ±0.175), (0.693 ±0.101), (0.094 ±0.012), (0.354 ±0.045), (0.201 ±0.037) mg/L, t_1/2 were (4.691 ±0.337), (5.62 ±1.64), (6.408 ±0.707), (4.103 ±0.341), (6.048 ±0.882), (5.803 ±0.59) h, AUC_(0-t) were (5.191 ±1.046), (6.168 ±1.25), (4.293 ±0.823), (0.485 ±0.103), (1.84 ±0.432), (0.924 ±0.19) mg·h/L. Contrast with Qikui Granules, relative bioavailability of morroniside, loganin, astragaloside, rutin, hyperin, and isoquerctirin in Qikui Sustained-release Tablets were 169.1%, 213.3%, 206.5%, 156.0%, 169.3%, and 186.3%, respectively. Conclusion Qikui Sustained-release Tablets can significantly improve the bioavailability of each active ingredient in rabbit.