普朗尼克F68对地西泮在大鼠小肠吸收过程的影响
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摘要
目的:考察药用辅料普朗尼克F68对地西泮在大鼠小肠吸收过程的影响。方法:采用大鼠在体单向肠灌流模型,使用HPLC法测定肠灌流液中地西泮浓度。计算不含普朗尼克F68药物组及含不同浓度普朗尼克F68药物组、含P-糖蛋白抑制药物组(维拉帕米)地西泮的吸收速率常数Ka与药物渗透系数Peff。结果:1. 00μg·ml~(-1)、0. 50μg·ml~(-1)的普朗尼克F68及维拉帕米均显著影响地西泮的K_a、P_(eff),并且随着普朗尼克F68浓度的增加,地西泮的K_a、P_(eff)相应增加。30μg·ml~(-1)的普朗尼克F68对地西泮无显著性影响。结论:0. 50μg·ml~(-1)和1. 00μg·ml~(-1)的普朗尼克F68药物组及维拉帕米组均显著增加地西泮在大鼠小肠的吸收,可能与其抑制P-糖蛋白有关。
Objective: To study the effect of Pluronic~() F68 on the intestinal absorption of diazepam in rats. Methods: Using single-pass intestinal perfusion model,the concentration of diazepam was determined by HPLC. The drug absorption rate constant(Ka) and the effective intestinal permeability(Peff) in each intestinal section were calculated in rats with or without Pluronic~() F68,or with P-gp inhibitor verapamil. Results: Pluronic~()F68( 1. 00 μg · ml~(-1),0. 05 μg·ml~(-1)) and varapamil signifcantly increased the Kaand Peffof diazepam,the Kaand Peffof diazepam was increased significantly when the concentration of diazepam was increased. On the other hand,the Kaand Peffof 30 μg·ml-1Pluronic~() F68 group was not affected significantly. Conclusion:Pluronic~() F68 at the doses of 0. 50 μg·ml~(-1) and 1. 00 μg·ml~(-1) and verapamil can promote the intestinal absorption of diazepam in rats,which may be due to the inhibition of P-glycoprotein activity.
Objective: To study the effect of Pluronic~() F68 on the intestinal absorption of diazepam in rats. Methods: Using single-pass intestinal perfusion model,the concentration of diazepam was determined by HPLC. The drug absorption rate constant(Ka) and the effective intestinal permeability(Peff) in each intestinal section were calculated in rats with or without Pluronic~() F68,or with P-gp inhibitor verapamil. Results: Pluronic~()F68( 1. 00 μg · ml~(-1),0. 05 μg·ml~(-1)) and varapamil signifcantly increased the Kaand Peffof diazepam,the Kaand Peffof diazepam was increased significantly when the concentration of diazepam was increased. On the other hand,the Kaand Peffof 30 μg·ml-1Pluronic~() F68 group was not affected significantly. Conclusion:Pluronic~() F68 at the doses of 0. 50 μg·ml~(-1) and 1. 00 μg·ml~(-1) and verapamil can promote the intestinal absorption of diazepam in rats,which may be due to the inhibition of P-glycoprotein activity.
引文
1杨晓波,刘克辛.P-糖蛋白分子结构及转运机制[J].药物评价研究,2018,41(1):1-4
2 Murakami T.Absorption sites of orally administered drugs in the small intestine[J].Expert Opin Drug Discov,2017,12(12):1219-1232
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9于洋,严子玲,赖巧,等.五味子配伍对吴茱萸主成分在大鼠肠道吸收中的影响研究[J].中国药师,2014,17(3):349-352
10闫涛,姜维,王琴会,等.苦参碱和甘草酸的小肠吸收特性分析[J].中国药师,2017,20(11):1906-1910
11黄建耿,斯陆勤,左克源,等.普朗尼克抑制P-糖蛋白药泵的作用[J].药学学报,2007,42(9):989-994
12 Chen T,Li Y,Li C,et al.Pluronic P85/F68 Micelles of Baicalein Could Interfere with Mitochondria to Overcome MRP2-Mediated Efflux and Offer Improved Anti-Parkinsonian Activity[J].Mol Pharm,2017,14(10):3331-3342
13 Liu J,He Y,Zhang J,et al.Functionalized nanocarrier combined seizure-specific vector with P-glycoprotein modulation property for antiepileptic drug delivery[J].Biomaterials,2016,74:64-76
14 Lima SA,Cordeiro-da-Silva A,De Castro B,et al.Benzodiazepine-mediated structural changes in the multidrug transporter P-glycoprotein:an intrinsic fluorescence quenching analysis[J].J Membr Biol,2008,223(3):117-225
15 Ho GT,Moodie FM,Satsangi J.Multidrug resistance 1 gene(p-glycoprotein 170):an important determinant in gastrointestinal disease[J].Gut,2003,52(5):759-766
2 Murakami T.Absorption sites of orally administered drugs in the small intestine[J].Expert Opin Drug Discov,2017,12(12):1219-1232
3 Wang MY,Yang M,Hou PY,et al.Intestinal absorption of pallidifloside D are limited by P-glycoprotein in mice[J].Xenobiotica,2018,48(7):739-744
4 Damont A,Goutal S,Auvity S,et al.Imaging the impact of cyclosporin A and dipyridamole on P-glycoprotein(ABCB1)function at the blood-brain barrier:A[(11)C]-N-desmethyl-loperamide PET study in nonhuman primates[J].Eur J Pharm Sci,2016,91:98-104
5 Palmeira A,Sousa E,Vasconcelos MH,et al.Three decades of P-gp inhibitors:skimming through several generations and scaffolds[J].Curr Med Chem,2012,19(13):1946-2025
6 Bansal T,Akhtar N,Jaggi M,et al.Novel formulation approaches for optimising delivery of anticancer drugs based on P-glycoprotein modulation[J].Drug Discov Today,2009,14(21):1067-74
7 Kabanov AV,Batrakova EV,Miller DW.Pluronic block copolymers as modulators of drug efflux transporter activity in the blood-brain barrier[J].Adv Drug Deliv Rev,2003,55(1):151-164
8 Yang X,Liu K.P-gp Inhibition-Based Strategies for Modulating Pharmacokinetics of Anticancer Drugs:An Update[J].Curr Drug Metab,2016,17(8):806-826
9于洋,严子玲,赖巧,等.五味子配伍对吴茱萸主成分在大鼠肠道吸收中的影响研究[J].中国药师,2014,17(3):349-352
10闫涛,姜维,王琴会,等.苦参碱和甘草酸的小肠吸收特性分析[J].中国药师,2017,20(11):1906-1910
11黄建耿,斯陆勤,左克源,等.普朗尼克抑制P-糖蛋白药泵的作用[J].药学学报,2007,42(9):989-994
12 Chen T,Li Y,Li C,et al.Pluronic P85/F68 Micelles of Baicalein Could Interfere with Mitochondria to Overcome MRP2-Mediated Efflux and Offer Improved Anti-Parkinsonian Activity[J].Mol Pharm,2017,14(10):3331-3342
13 Liu J,He Y,Zhang J,et al.Functionalized nanocarrier combined seizure-specific vector with P-glycoprotein modulation property for antiepileptic drug delivery[J].Biomaterials,2016,74:64-76
14 Lima SA,Cordeiro-da-Silva A,De Castro B,et al.Benzodiazepine-mediated structural changes in the multidrug transporter P-glycoprotein:an intrinsic fluorescence quenching analysis[J].J Membr Biol,2008,223(3):117-225
15 Ho GT,Moodie FM,Satsangi J.Multidrug resistance 1 gene(p-glycoprotein 170):an important determinant in gastrointestinal disease[J].Gut,2003,52(5):759-766