雷公藤固体分散体大鼠在体肠吸收研究
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摘要
目的研究雷公藤固体分散体的大鼠肠吸收动力学特征,考察不同肠段、药物浓度、pH值和P-糖蛋白(P-gp)对肠吸收的影响。方法采用大鼠在体单向肠灌流模型,HPLC法测定各指标成分含量,重量法校正数据并计算各指标成分的吸收速率常数(Ka)和表观渗透系数(Papp)。结果将原料药制成固体分散体后,雷公藤各成分在全肠段的Ka较原料药显著增大(P<0.05),雷公藤各指标成分在各肠段均有吸收且存在一定差异。随着药物浓度的升高,各指标成分的吸收均具有饱和现象。酸性环境(pH5.4)有利于各指标成分的吸收,尤其是酸性成分雷公藤红素。加入P-gp抑制剂后,雷公藤红素的吸收与不加P-gp抑制剂比较有显著差异(P<0.05),可能为P-gp底物。结论雷公藤固体分散体各指标成分在全肠段均有吸收,且具有饱和现象;酸性环境有利于各成分的吸收,雷公藤红素吸收过程受药物浓度和P-gp的外排影响,可能为P-gp底物;制成固体分散体能显著提高雷公藤各成分的吸收,提示各指标成分均为生物药剂学系统II类药物,制剂研发过程中增加药物溶解度或可提高制剂的生物利用度。
Objective To study the intestinal absorption kinetics of Tripterygium wilfordii(TW) solid dispersions and the effects of different intestinal segments,drug concentrations,pH value,and P-glycoprotein(P-gp) on intestinal absorption.Methods The absorption behavior was investigated in situ with a single-pass intestinal perfusion(SPIP) model in rats.The content of each index component was determined by HPLC.The gravimetric method was used to correct the data and calculate the absorption rate constant(Ka) and apparent permeability coefficient(Papp) of each index component.Results The index components of TW were absorbed in the whole intestine,and the absorption rate constant(Ka) of all the index components of TW solid dispersion was significantly increased than that of extract(P < 0.05),and had some differences among different segments.With the increase of drug concentration,the absorption of each index component had saturation phenomenon,which indicated that it may be carrier-mediated transport mechanism.Acidic environment(pH 5.4) was beneficial to the absorption of various index components,especially the acidic content celastrol.After adding P-gp inhibitor,the Ka and Papp of celastrol were significantly different from those without P-gp inhibitor(P < 0.05),which suggested that it may be the P-gp substrate.Conclusion All the index components of TW solid dispersion are absorbed in the whole intestine and have saturation phenomenon,which suggested the absorption may be carrier-mediated transport mechanism.Acidic environment is beneficial to the absorption of all components.The absorption process of celastrol is affected by drug concentration and P-gp inhibitor,which indicated that it may be P-gp substrate.The preparation of solid dispersing can significantly enhance the absorption of various components of TW,suggesting that all the index components are BCS II drugs,and the bioavailability of the preparation may be improved.
Objective To study the intestinal absorption kinetics of Tripterygium wilfordii(TW) solid dispersions and the effects of different intestinal segments,drug concentrations,pH value,and P-glycoprotein(P-gp) on intestinal absorption.Methods The absorption behavior was investigated in situ with a single-pass intestinal perfusion(SPIP) model in rats.The content of each index component was determined by HPLC.The gravimetric method was used to correct the data and calculate the absorption rate constant(Ka) and apparent permeability coefficient(Papp) of each index component.Results The index components of TW were absorbed in the whole intestine,and the absorption rate constant(Ka) of all the index components of TW solid dispersion was significantly increased than that of extract(P < 0.05),and had some differences among different segments.With the increase of drug concentration,the absorption of each index component had saturation phenomenon,which indicated that it may be carrier-mediated transport mechanism.Acidic environment(pH 5.4) was beneficial to the absorption of various index components,especially the acidic content celastrol.After adding P-gp inhibitor,the Ka and Papp of celastrol were significantly different from those without P-gp inhibitor(P < 0.05),which suggested that it may be the P-gp substrate.Conclusion All the index components of TW solid dispersion are absorbed in the whole intestine and have saturation phenomenon,which suggested the absorption may be carrier-mediated transport mechanism.Acidic environment is beneficial to the absorption of all components.The absorption process of celastrol is affected by drug concentration and P-gp inhibitor,which indicated that it may be P-gp substrate.The preparation of solid dispersing can significantly enhance the absorption of various components of TW,suggesting that all the index components are BCS II drugs,and the bioavailability of the preparation may be improved.
引文
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[19]Zhou J,Ma Y H,Zhou Z,et al.Intestinal absorption and metabolism of epimedium flavonoids in osteoporosis rats[J].Drug Metabol Disposit,2015,43(10):1590-1600.
[20]Zhou W,Tan X,Shan J,et al.Study on the main components interaction from Flos Lonicerae and Fructus Forsythiae and their dissolution in vitro and intestinal absorption in rats[J].PLo S One,2014,9(10):e109619.
[21]关志宇,张丽华,陈丽华,等.贝母提取物中贝母甲素和贝母乙素的大鼠肠吸收特性[J].药学学报,2013,48(12):1836-1843.
[22]罗见春,何丹,杨梅,等.去甲氧基姜黄素羟丙基-β-环糊精在体肠吸收特征[J].第二军医大学学报,2016(2):247-250.
[23]顾念,沈昕怡,秦超,等.他克莫司固体分散体的制备及肠吸收研究[J].中国药科大学学报,2016,47(6):694-701.
[24]晏声蕾,胡江波,王薛,等.吴茱萸碱油包水型复合纳米乳的药代动力学和在体肠吸收[J].第二军医大学学报,2017,38(2):249-252.
[25]张艳,王平,王进荣,等.在体单向肠灌流模型研究大黄素的大鼠肠吸收特性[J].中药新药与临床药理,2012,23(3):286-290.
[26]张燕,朱华旭,郭立玮.在体单向肠灌流模型研究小檗碱及其在复方配伍环境中的大鼠肠吸收特性[J].药学学报,2012,47(2):233-238.
[27]薛璟.雷公藤主成分肠吸收动力学研究[D].南京:南京中医药大学,2010.
[28]Stappaerts J,Brouwers J,Annaert P,et al.In situ perfusion in rodents to explore intestinal drug absorption:Challenges and opportunities[J].Inter J Pharm,2015,478(2):665-681.
[29]Li H,Dong L,Liu Y,et al.Comparison of two approaches of intestinal absorption by puerarin[J].JPharmacol Toxicol,2014,70(1):6-11.
[30]聂淑芳,潘卫三,杨星钢,等.对大鼠在体肠单向灌流技术中重量法的评价[J].中国新药杂志,2005,14(10):1176-1179.
[31]张慧敏.贝母甲素性别差异药动学研究[D].南昌:江西中医药大学,2013.
[32]雷晴.昆明山海棠与雷公藤急性毒性及对DHT反应影响的对比研究[D].昆明:昆明医学院,2006.
[2]昊霞,林兵,王忠震,等.雷公藤的免疫抑制活性及毒性的谱效关系研究[J].中国医院药学杂志,2016,35(7):547-552.
[3]胡德俊,彭泽燕,何东初.雷公藤的药理作用研究进展[J].医药导报,2018,37(5):586-592.
[4]刘素晓,闫凤娜,王幼平.雷公藤多苷的抗炎作用与临床应用进展[J].中医临床研究,2017(32):131-134.
[5]Xu X,Li Q J,Xia S,et al.Tripterygium glycosides for treating late-onset rheumatoid arthritis:A systematic review and Meta-analysis[J].Altern Ther Health Med,2016,22(6):32-39.
[6]Zhu B,Wang Y,Jardine M,et al.Tripterygium preparations for the treatment of CKD:A systematic review and meta-analysis[J].Am J Kidney Dis,2013,62(3):515-530.
[7]孙萍萍,张天娇,许可嘉,等.雷公藤及其制剂临床不良反应分布特点随机对照试验的系统评价[J].世界科学技术-中医药现代化,2015,17(9):1899-1905.
[8]张玉萌,朱丽萍.雷公藤制剂致肝毒性、生殖毒性和血液系统毒性不良反应回顾性分析[J].中国药物应用与监测,2014,11(3):173-176.
[9]刘雪梅,刘志宏,张晶,等.雷公藤临床应用及不良反应的研究进展[J].药学实践杂志,2015,33(2):110-113.
[10]罗岚,江振洲,张陆勇.雷公藤多苷肝毒性发生机制及减毒相关研究进展[J].药物评价研究,2017,40(10):1504-1509
[11]霍涛涛,张美敬,陶春,等.基于多组分评价的雷公藤提取物固体分散体的制备及体外表征[J].中草药,2018,49(1):128-134.
[12]刘建平.生物药剂学与药物动力学[M].第5版.北京:人民卫生出版社,2016.
[13]Sun Y,He X,Yang X,et al.Absorption characteristics of the total alkaloids from Mahonia bealei in an in situ single-pass intestinal perfusion assay[J].Chin J Nat Med,2014,12(7):554-560.
[14]Li Y,Zhang R,Peng C.Assessment and modulation of forsythiaside absorption with MDCKII cells and validation with in situ intestinal experiment[J].Eur JDrug Metab Ph,2012,37(3):179-186.
[15]Xie Y,Zeng X,Li G,et al.Assessment of intestinal absorption of total flavones of Hippophae rhamnoides L.in rat using in situ absorption models[J].Drug Dev Ind Pharm,2010,36(7):787-794.
[16]Iwanaga K,Arimune K,Miyazaki M,et al.Effects of furanocoumarins in Kampo extract-based medicines on rat intestinal absorption of CYP3A and P-glycoprotein substrate drugs in vivo[J].Arch Pharm Res,2012,35(6):1055-1064.
[17]Fong Y K,Li C R,Wo S K,et al.In vitro and in situ evaluation of herb-drug interactions during intestinal metabolism and absorption of baicalein[J].JEthnopharm,2012,141(2):742-753.
[18]Zhou Y J,Qin D P,Wang Y D,et al.Amelioration of tripterygium wilfordii polycoride on TNBS/ethanolinduced ulcerative colitis via inhibiting lipid peroxidation and its downstream inflammatory meditors[J].Chin Herb Med,2017,9(4):344-352.
[19]Zhou J,Ma Y H,Zhou Z,et al.Intestinal absorption and metabolism of epimedium flavonoids in osteoporosis rats[J].Drug Metabol Disposit,2015,43(10):1590-1600.
[20]Zhou W,Tan X,Shan J,et al.Study on the main components interaction from Flos Lonicerae and Fructus Forsythiae and their dissolution in vitro and intestinal absorption in rats[J].PLo S One,2014,9(10):e109619.
[21]关志宇,张丽华,陈丽华,等.贝母提取物中贝母甲素和贝母乙素的大鼠肠吸收特性[J].药学学报,2013,48(12):1836-1843.
[22]罗见春,何丹,杨梅,等.去甲氧基姜黄素羟丙基-β-环糊精在体肠吸收特征[J].第二军医大学学报,2016(2):247-250.
[23]顾念,沈昕怡,秦超,等.他克莫司固体分散体的制备及肠吸收研究[J].中国药科大学学报,2016,47(6):694-701.
[24]晏声蕾,胡江波,王薛,等.吴茱萸碱油包水型复合纳米乳的药代动力学和在体肠吸收[J].第二军医大学学报,2017,38(2):249-252.
[25]张艳,王平,王进荣,等.在体单向肠灌流模型研究大黄素的大鼠肠吸收特性[J].中药新药与临床药理,2012,23(3):286-290.
[26]张燕,朱华旭,郭立玮.在体单向肠灌流模型研究小檗碱及其在复方配伍环境中的大鼠肠吸收特性[J].药学学报,2012,47(2):233-238.
[27]薛璟.雷公藤主成分肠吸收动力学研究[D].南京:南京中医药大学,2010.
[28]Stappaerts J,Brouwers J,Annaert P,et al.In situ perfusion in rodents to explore intestinal drug absorption:Challenges and opportunities[J].Inter J Pharm,2015,478(2):665-681.
[29]Li H,Dong L,Liu Y,et al.Comparison of two approaches of intestinal absorption by puerarin[J].JPharmacol Toxicol,2014,70(1):6-11.
[30]聂淑芳,潘卫三,杨星钢,等.对大鼠在体肠单向灌流技术中重量法的评价[J].中国新药杂志,2005,14(10):1176-1179.
[31]张慧敏.贝母甲素性别差异药动学研究[D].南昌:江西中医药大学,2013.
[32]雷晴.昆明山海棠与雷公藤急性毒性及对DHT反应影响的对比研究[D].昆明:昆明医学院,2006.