葛根素体内药动学及葛根黄酮自微乳化软胶囊的研究
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摘要
葛根素是中药葛根的主要成分，临床上广泛用于治疗心血管疾病。本文旨在研究葛根素在肠粘膜的吸收性质及肝脏的首过效应，从而阐明影响口服吸收的因素；研究其他药物对葛根素药动学的影响，从而为临床上合理用药提供依据；研究制备葛根黄酮自微乳化软胶囊，并对其体内药动学过程进行了研究。
首先，以外翻肠囊法考察了葛根素在肠粘膜的吸收性质。葛根素在空肠、回肠和结肠的吸收均具有自身浓度抑制作用，表明葛根素在各肠段的吸收有可能存在主动转运的过程。pH值对葛根素在肠粘膜的透过性没有显著性影响。吐温-80和二乙二醇单乙醚(Transcutol P)对葛根素的肠吸收具有一定的促进作用。1，2-丙二醇对葛根素的肠吸收无显著性影响。随着P-糖蛋白抑制剂地高辛和维拉帕米浓度的增大，葛根素的肠粘膜透过性增强，当浓度分别达到50μg／ml和200μg／ml时，这种作用具有一定的饱和性，证明葛根素的肠吸收存在主动转运过程。
以Caco-2细胞为模型考察了葛根素在肠粘膜的透过性。葛根素在Caco-2细胞的转运呈现较强的方向性，随着葛根素浓度的增加，其表观渗透率(PDR)降低(2.1～1.4)。随着温度升高表观渗透率增大。当加入代谢抑制剂KCN和2,4-二硝基苯酚时，葛根素的表观渗透率降低(由1.7分别降至1.0和1.2)。当加入100μg／ml维拉帕米时，A面到B面的表观渗透系数Papp(A→B)从0.84±0.18×10~(-7)cm／s增加到1.01±0.17×10~(-7)cm／s，而B面到A面的Papp(B→A)从1.43±0.18×10~(-7)cm／s降低到1.11±0.24×10~(-7)cm／s。通过外翻肠囊法和Caco-2细胞法研究证明葛根素经肠粘膜的转运可能存在外排泵P-糖蛋白的作用。
采用离体大鼠肝灌流技术测定了不同浓度葛根素(1，10和50μg／ml)在肝脏的消除率分别为0.511±0.045、0.378±0.026、0.425±0.040ml／min。不同类型药物对葛根素肝脏消除率影响不同，如维拉帕米和红霉素对葛根素在大鼠离体肝脏的消除有抑制作用；利福平对葛根素在大鼠离体肝脏的消除有促进作用；硝苯地平和3-正丁基苯酞对葛根素的消除无显著性影响。
制备了大鼠和豚鼠的肝微粒体，建立了肝微粒体体外代谢研究模型，对葛根素代谢进行了研究。随着肝微粒体蛋白浓度的增大，葛根素呈线性消除。葛根素可被肝微粒体代谢成大豆甙元(40min时不足原药葛根素量的1％)，其代谢机理为NADPH依赖性的氧化代谢。NADH对葛根素代谢基本没有催化作用，在大鼠肝微粒体中，葛根素和大豆甙元可与CYP450形成抑制性复合物。葛根素在大鼠和豚鼠肝微粒体中的代谢率无显著性差别。
采用HPLC法研究了一些药物与葛根素联合用药后在大鼠体内对葛根素药动学的影响。静脉用药时，低剂量的乳糖酸红霉素和维拉帕米对葛根素从大鼠体内
Puerarin is one of the main active constituents of Pueraria lobata, and it has been used for the treatment of senile ischemic cerebrovascular disease.
The main objectives of this research were to study the intestinal absorption and first-pass effect of puerarin, pharmacokinetic changes of coadministration with other drugs in rats, to prepare the Self-microemulsifying drug delivery systems (SMEDDS) of Pueraria lobata and to research its pharmacokinetics in different animals.
The intestinal transport of puerarin was performed by applying everted intestinal sacs method. With an increase of the concentration of puerarin, puerarin absorption across intestinal membrane was increased in the rat jejunum, ileum and colon, but there exited a saturable transport process for puerarin. pH values didn't affect intestinal absorption of puerarin in different sacs. Tween-80 and Transcutol P increased the intestinal absorption of puerarin, and 1,2-Propanediol had no effect on the intestinal absorption of puerarin. With an increase of the concentration of verapamil and digoxin, puerarin absorption across intestinal membrane increased in the rat jejunum, ileum and colon, but when the concentration of digoxin and verapamil was 50 and 200 μg/ml, the increase had a saturable process, so it was indicated that the transport of puerarin across intestinal membrane was mediated by efflux transport.
The Caco-2 cell model was used to study the transport of puerarin across the intestinal membrane. The transport of puerarin across Caco-2 cell monolayers was directional. With the increase of the concentration of puerarin, the permeability coefficient ratio (PDR) was decreased from 2.1 to 1.4. With the increase of temperature, PDR was increased. When KCN and 2,4-dinitrophenol were added, the permeability coefficient ratio was decreased from 1.7 to 1.0 and 1.2, respectively. When 100 μg/ml verapamil was added, the permeability coefficient of apical to basolateral was increased from 0.84±0.18×10~(-7) cm/s to 1.01 ±0.17×10~(-7) cm/s, and the permeability coefficient of basolateral to apical was decreased from 1.43±0.18×10~(-7) cm/s to 1.11 ±0.24×10~(-7) cm/s. From the everted intestinal sacs and Caco-2 cell models, it was proved that puerarin was transported across intestinal membrane by efflux pump-P-glyprotein.
The hepatic clearance of puerarin during isolated rat liver perfusion were 0.511 ±
首先，以外翻肠囊法考察了葛根素在肠粘膜的吸收性质。葛根素在空肠、回肠和结肠的吸收均具有自身浓度抑制作用，表明葛根素在各肠段的吸收有可能存在主动转运的过程。pH值对葛根素在肠粘膜的透过性没有显著性影响。吐温-80和二乙二醇单乙醚(Transcutol P)对葛根素的肠吸收具有一定的促进作用。1，2-丙二醇对葛根素的肠吸收无显著性影响。随着P-糖蛋白抑制剂地高辛和维拉帕米浓度的增大，葛根素的肠粘膜透过性增强，当浓度分别达到50μg／ml和200μg／ml时，这种作用具有一定的饱和性，证明葛根素的肠吸收存在主动转运过程。
以Caco-2细胞为模型考察了葛根素在肠粘膜的透过性。葛根素在Caco-2细胞的转运呈现较强的方向性，随着葛根素浓度的增加，其表观渗透率(PDR)降低(2.1～1.4)。随着温度升高表观渗透率增大。当加入代谢抑制剂KCN和2,4-二硝基苯酚时，葛根素的表观渗透率降低(由1.7分别降至1.0和1.2)。当加入100μg／ml维拉帕米时，A面到B面的表观渗透系数Papp(A→B)从0.84±0.18×10~(-7)cm／s增加到1.01±0.17×10~(-7)cm／s，而B面到A面的Papp(B→A)从1.43±0.18×10~(-7)cm／s降低到1.11±0.24×10~(-7)cm／s。通过外翻肠囊法和Caco-2细胞法研究证明葛根素经肠粘膜的转运可能存在外排泵P-糖蛋白的作用。
采用离体大鼠肝灌流技术测定了不同浓度葛根素(1，10和50μg／ml)在肝脏的消除率分别为0.511±0.045、0.378±0.026、0.425±0.040ml／min。不同类型药物对葛根素肝脏消除率影响不同，如维拉帕米和红霉素对葛根素在大鼠离体肝脏的消除有抑制作用；利福平对葛根素在大鼠离体肝脏的消除有促进作用；硝苯地平和3-正丁基苯酞对葛根素的消除无显著性影响。
制备了大鼠和豚鼠的肝微粒体，建立了肝微粒体体外代谢研究模型，对葛根素代谢进行了研究。随着肝微粒体蛋白浓度的增大，葛根素呈线性消除。葛根素可被肝微粒体代谢成大豆甙元(40min时不足原药葛根素量的1％)，其代谢机理为NADPH依赖性的氧化代谢。NADH对葛根素代谢基本没有催化作用，在大鼠肝微粒体中，葛根素和大豆甙元可与CYP450形成抑制性复合物。葛根素在大鼠和豚鼠肝微粒体中的代谢率无显著性差别。
采用HPLC法研究了一些药物与葛根素联合用药后在大鼠体内对葛根素药动学的影响。静脉用药时，低剂量的乳糖酸红霉素和维拉帕米对葛根素从大鼠体内
Puerarin is one of the main active constituents of Pueraria lobata, and it has been used for the treatment of senile ischemic cerebrovascular disease.
The main objectives of this research were to study the intestinal absorption and first-pass effect of puerarin, pharmacokinetic changes of coadministration with other drugs in rats, to prepare the Self-microemulsifying drug delivery systems (SMEDDS) of Pueraria lobata and to research its pharmacokinetics in different animals.
The intestinal transport of puerarin was performed by applying everted intestinal sacs method. With an increase of the concentration of puerarin, puerarin absorption across intestinal membrane was increased in the rat jejunum, ileum and colon, but there exited a saturable transport process for puerarin. pH values didn't affect intestinal absorption of puerarin in different sacs. Tween-80 and Transcutol P increased the intestinal absorption of puerarin, and 1,2-Propanediol had no effect on the intestinal absorption of puerarin. With an increase of the concentration of verapamil and digoxin, puerarin absorption across intestinal membrane increased in the rat jejunum, ileum and colon, but when the concentration of digoxin and verapamil was 50 and 200 μg/ml, the increase had a saturable process, so it was indicated that the transport of puerarin across intestinal membrane was mediated by efflux transport.
The Caco-2 cell model was used to study the transport of puerarin across the intestinal membrane. The transport of puerarin across Caco-2 cell monolayers was directional. With the increase of the concentration of puerarin, the permeability coefficient ratio (PDR) was decreased from 2.1 to 1.4. With the increase of temperature, PDR was increased. When KCN and 2,4-dinitrophenol were added, the permeability coefficient ratio was decreased from 1.7 to 1.0 and 1.2, respectively. When 100 μg/ml verapamil was added, the permeability coefficient of apical to basolateral was increased from 0.84±0.18×10~(-7) cm/s to 1.01 ±0.17×10~(-7) cm/s, and the permeability coefficient of basolateral to apical was decreased from 1.43±0.18×10~(-7) cm/s to 1.11 ±0.24×10~(-7) cm/s. From the everted intestinal sacs and Caco-2 cell models, it was proved that puerarin was transported across intestinal membrane by efflux pump-P-glyprotein.
The hepatic clearance of puerarin during isolated rat liver perfusion were 0.511 ±
引文
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[1] USP2807651.
[2] 精细有机化工手册．
[3] 精细有机化工手册．
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[1] Inoue, Hiroki; Yokota, Hiroshi; Makino, Tsunehisa; Yuasa, Akira; Kato, Seiyu. Bisphenol A glucuronide, a major metabolite in rat bile after liver perfusion.Drug Metab. Dispos., 2001, 29(8):1084-1087.
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[12] Yamazaki, Masayo; Kobayashi, Kazuo; Sugiyama, Yuichi. Primary active transport of pravastatin across the liver canalicular membrane in normal and mutant Eisai hyperbilirubinemi1 rats. Biopharm. Drug Dispos., 1996, 17(8):645-659.
[13] Takino, Toichi; Nagahama, Eiko; Kakutani, Toshiyuki Sakaedanee; Yamashita, Fumiyoshi; Takakura, Yoshinobu; Hashida, Mitsuru. Pharmacokinetic disposition analysis of lipophilic drugs injected with various lipid carriers in the single-pass rat liver perfusion system. Int. J. Pharm., 1995, 114(1):43-54.
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[16] Sang Baek Koh; Bong Suk Cha; Jong Ku Park; Soung Hoon Chang; Sei Jin Chang. The metabolism and liver toxicity of N,N-dimethylformamide in the isolated rat liver. Yonsei Medical Journal, 2002, 43(4):491-499.
[17] 印绮平，奚念朱，王宏图，张静华．适于研究药物相互作用的肝脏灌流模型．中国临床药学杂志，1999，8(1)：36-39．
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[1] USP2807651.
[2] 精细有机化工手册．
[3] 精细有机化工手册．
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[1] 徐贵霞，王玉丽，全东琴．自乳化释药系统的体外评价．解放军药学学报，2003，19(3)：195-197．
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