芪葵缓释片中6种活性成分在兔血浆中的药动学研究
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摘要
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。
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 ×10-3 X-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, t1/2 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, t1/2 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.
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 ×10-3 X-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, t1/2 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, t1/2 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.
引文
[1]黄莉吉,余江毅,朱博钰,等.“芪葵颗粒”联合西医常规疗法治疗早期糖尿病肾病31例临床研究[J].江苏中医药,2017,49(4):29-31.
[2]严倩华.芪葵颗粒治疗早期糖尿病肾病疗效观察及其对肾小管上皮细胞EMT影响的机制研究[D].南京:南京中医药大学,2018.
[3]姜静岩,尹晓飞,王书杰,等.黄芪甲苷对糖尿病模型大鼠造影剂肾损伤的保护作用[J].解放军药学学报,2017,33(3):218-221.
[4]陈廷芳,郭永平,桂定坤,等.黄芪甲苷干预高糖诱导的足细胞转分化的体外研究[J].中国中西医结合肾病杂志,2017,18(6):482-485.
[5]许惠琴,朱荃.山茱萸环烯醚萜总苷对实验性糖尿病肾病变的保护作用[J].南京中医药大学学报:自然科学版,2003,19(6):342-345.
[6]段煜,裴科,蔡皓,等.以黄芪-山茱萸治疗糖尿病肾病为例探究药对研究的新策略[J].中国中药杂志,2016,41(21):3919-3926.
[7]陈萍,万毅刚,王朝俊,等.黄蜀葵花制剂治疗慢性肾脏病的机制和疗效[J].中国中药杂志,2012,37(15):2252-2256.
[8]Chang X,Guo G,Fan Z,et al.Simultaneous determination of two bioactive components of Huangqi Guizhi Wuwu Decoction in rat plasma using UPLC-MS/MS and its application to a pharmacokinetic study[J].J Chin Pharm Sci,2018,27(4):263-272.
[9]韩根利,刘宏胜,王树森,等.RP-HPLC法同时测定山茱萸萜类制剂中莫诺苷、马钱苷、山茱萸新苷、齐墩果酸及熊果酸[J].中草药,2017,48(24):5168-5173.
[10]池玉梅,朱华云,居羚,等.高效液相-四极杆飞行时间串联质谱分析黄蜀葵花中黄酮醇类化合物[J].分析化学,2009,37(2):227-231.
[11]李小娜,王巧,张兰桐,等.山茱萸中马钱苷在大鼠体内的药物动力学研究[J].药物分析杂志,2007,27(1):4-7.
[12]蔡源源,孙华,王玮,等.醋柳黄酮缓释片的药动学初步研究[J].河南大学学报,2008,27(4):36-39.
[13]曹小帅,沙美,欧阳强,等.黄蜀葵花中4种黄酮类成分体内整合药动学研究[J].中草药,2010,41(2):255-259.
[14]陆林玲,钱大玮,郭建明,等.一测多评法测定黄蜀葵花中7个黄酮类成分[J].药物分析杂志,2013,33(12):2082-2087.
[15]杨秀岭,袁志芳,张兰桐,等.照山白总黄酮中杨梅苷、金丝桃苷和槲皮苷在大鼠体内的药动学[J].中国医院药学杂志,2009,29(19):1610-1614.
[16]Ma Y M,Xie H,Zhu S M,et al.Pharmacokinetics of astragalosideⅣin rabbits and its excretion in rats[J].Chin J New Drugs Clin Rem,2004,23(9):563-566.
[17]杨素芹,刘文惠,张继敏,等.液相色谱-串联质谱法测定大鼠血浆中黄芪甲苷及其药动学[J].中国新药与临床杂志,2011,30(9):705-709.
[18]Yan L X,Guo D A.Quantitation of astragaloside IV in rat plasma by liquid chromatography-tandem mass spectrometry[J].J Chromatogr B Anal Technol Biomed Life Sci,2005,824(1):244-248.
[2]严倩华.芪葵颗粒治疗早期糖尿病肾病疗效观察及其对肾小管上皮细胞EMT影响的机制研究[D].南京:南京中医药大学,2018.
[3]姜静岩,尹晓飞,王书杰,等.黄芪甲苷对糖尿病模型大鼠造影剂肾损伤的保护作用[J].解放军药学学报,2017,33(3):218-221.
[4]陈廷芳,郭永平,桂定坤,等.黄芪甲苷干预高糖诱导的足细胞转分化的体外研究[J].中国中西医结合肾病杂志,2017,18(6):482-485.
[5]许惠琴,朱荃.山茱萸环烯醚萜总苷对实验性糖尿病肾病变的保护作用[J].南京中医药大学学报:自然科学版,2003,19(6):342-345.
[6]段煜,裴科,蔡皓,等.以黄芪-山茱萸治疗糖尿病肾病为例探究药对研究的新策略[J].中国中药杂志,2016,41(21):3919-3926.
[7]陈萍,万毅刚,王朝俊,等.黄蜀葵花制剂治疗慢性肾脏病的机制和疗效[J].中国中药杂志,2012,37(15):2252-2256.
[8]Chang X,Guo G,Fan Z,et al.Simultaneous determination of two bioactive components of Huangqi Guizhi Wuwu Decoction in rat plasma using UPLC-MS/MS and its application to a pharmacokinetic study[J].J Chin Pharm Sci,2018,27(4):263-272.
[9]韩根利,刘宏胜,王树森,等.RP-HPLC法同时测定山茱萸萜类制剂中莫诺苷、马钱苷、山茱萸新苷、齐墩果酸及熊果酸[J].中草药,2017,48(24):5168-5173.
[10]池玉梅,朱华云,居羚,等.高效液相-四极杆飞行时间串联质谱分析黄蜀葵花中黄酮醇类化合物[J].分析化学,2009,37(2):227-231.
[11]李小娜,王巧,张兰桐,等.山茱萸中马钱苷在大鼠体内的药物动力学研究[J].药物分析杂志,2007,27(1):4-7.
[12]蔡源源,孙华,王玮,等.醋柳黄酮缓释片的药动学初步研究[J].河南大学学报,2008,27(4):36-39.
[13]曹小帅,沙美,欧阳强,等.黄蜀葵花中4种黄酮类成分体内整合药动学研究[J].中草药,2010,41(2):255-259.
[14]陆林玲,钱大玮,郭建明,等.一测多评法测定黄蜀葵花中7个黄酮类成分[J].药物分析杂志,2013,33(12):2082-2087.
[15]杨秀岭,袁志芳,张兰桐,等.照山白总黄酮中杨梅苷、金丝桃苷和槲皮苷在大鼠体内的药动学[J].中国医院药学杂志,2009,29(19):1610-1614.
[16]Ma Y M,Xie H,Zhu S M,et al.Pharmacokinetics of astragalosideⅣin rabbits and its excretion in rats[J].Chin J New Drugs Clin Rem,2004,23(9):563-566.
[17]杨素芹,刘文惠,张继敏,等.液相色谱-串联质谱法测定大鼠血浆中黄芪甲苷及其药动学[J].中国新药与临床杂志,2011,30(9):705-709.
[18]Yan L X,Guo D A.Quantitation of astragaloside IV in rat plasma by liquid chromatography-tandem mass spectrometry[J].J Chromatogr B Anal Technol Biomed Life Sci,2005,824(1):244-248.