桑黄素和乙酰化白藜芦醇对沙奎那韦在大鼠体内药代动力学的影响
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摘要
目的评估桑黄素和乙酰化白藜芦醇对大鼠体内沙奎那韦(P-gp作用底物)药物代谢动力学的影响。方法将SD大鼠分为4组,每组5只,即对照组、实验Ⅰ和Ⅱ组、阳性对照组,分别灌胃给予30 mg·kg-1沙奎那韦;30 mg·kg-1沙奎那韦联用40 mg·kg-1桑黄素;30 mg·kg-1沙奎那韦联用40 mg·kg-1乙酰化白藜芦醇和30 mg·kg-1沙奎那韦联用40 mg·kg-1维拉帕米。采用HPLC-MS/MS方法测定给药后不同时间沙奎那韦的血药浓度,计算药动学参数。结果 4组大鼠体内主要药动学参数分别为:AUC0-t:381.53μg·h·L~(-1),185.53μg·h·L~(-1),360.43μg·h·L~(-1),529.95μg·h·L~(-1);AUC0-∞:409.48μg·h·L~(-1),228.52μg·h·L~(-1),446.67μg·h·L~(-1),552.41μg·h·L~(-1);Cmax:110.80μg·L~(-1),86.44μg·L~(-1),139.84μg·L~(-1),423.60μg·L~(-1);Tmax:0.25 h,0.25 h,0.25 h,0.50 h;T1/2:5.72 h,5.94 h,6.78h,3.78 h;MRT0-∞:10.30 h,9.61 h,12.30 h,4.89 h;CL/F:7.59 m L·kg-1·h-1,13.88 m L·kg-1·h-1,7.28 m L·kg-1·h-1,5.52 m L·kg-1·h-1。结论沙奎那韦的药时曲线存在多峰现象;桑黄素可明显降低沙奎那韦的口服生物利用度并对其药动学参数产生影响,而乙酰化白藜芦醇对沙奎那韦的口服生物利用度和药动学参数没有明显影响。
Aim To assess the impact of morin and acetyl-resveratrol on the oral bioavailability and pharmacokinetics of saquinavir( SQV),a substrate of P-glycoprotein( P-gp),in rats. Methods Twenty rats were randomized into four groups of equal size,including a control group,two intervention groups and a positive control group,and administered orally 30 mg·kg~(-1) SQV with or without 40 mg·kg~(-1) morin or acetyl-resveratrol or verapamil( as positive control). The plasma concentrations of saquinavir were determined using a high-performance liquid chromatography-tandem mass spectrometry( HPLC-MS/MS) method,and the PK of SQV was assessed using non-compartmental analysis. Results The PK parameters values of SQV,SQV + morin,SQV + acetyl-resveratrol,SQV + verapamil were as follows: AUC_(0-t),381. 53 μg·h·L~(-1),185. 53 μg·h ·L~(-1),360. 43 μg·h·L~(-1),529. 95μg · h · L~(-1); AUC_(0-∞),409. 48 μg · h · L~(-1),228. 52 μg· h · L~(-1),446. 67 μg·h·L~(-1),552. 41μg·h·L~(-1); Cmax,110. 80 μg·L~(-1),86. 44 μg·L~(-1),139. 84 μg·L~(-1),423. 60 μg·L~(-1); Tmax,0. 25 h,0. 25 h,0. 25 h,0. 50 h; T1/2,5. 72 h,5. 94 h,6. 78 h,3. 78 h; MRT_(0-∞),10. 30 h,9. 61 h,12. 30 h,4. 89 h; CL/F,7. 59 m L·kg-1·h~(-1),13. 88 m L·kg-1·h~(-1),7. 28 m L·kg-1·h~(-1),5. 52 m L·kg-1·h~(-1). Conclusions Multiple peak phenomenon can be observed in the plasma SQV profiles. Morin can significantly reduce the SQV oral bioavailability and affect SQV PK profiles while acetyl-resveratrol cannot significantly affect the SQV oral bioavailability and SQV PK profiles in rats.
Aim To assess the impact of morin and acetyl-resveratrol on the oral bioavailability and pharmacokinetics of saquinavir( SQV),a substrate of P-glycoprotein( P-gp),in rats. Methods Twenty rats were randomized into four groups of equal size,including a control group,two intervention groups and a positive control group,and administered orally 30 mg·kg~(-1) SQV with or without 40 mg·kg~(-1) morin or acetyl-resveratrol or verapamil( as positive control). The plasma concentrations of saquinavir were determined using a high-performance liquid chromatography-tandem mass spectrometry( HPLC-MS/MS) method,and the PK of SQV was assessed using non-compartmental analysis. Results The PK parameters values of SQV,SQV + morin,SQV + acetyl-resveratrol,SQV + verapamil were as follows: AUC_(0-t),381. 53 μg·h·L~(-1),185. 53 μg·h ·L~(-1),360. 43 μg·h·L~(-1),529. 95μg · h · L~(-1); AUC_(0-∞),409. 48 μg · h · L~(-1),228. 52 μg· h · L~(-1),446. 67 μg·h·L~(-1),552. 41μg·h·L~(-1); Cmax,110. 80 μg·L~(-1),86. 44 μg·L~(-1),139. 84 μg·L~(-1),423. 60 μg·L~(-1); Tmax,0. 25 h,0. 25 h,0. 25 h,0. 50 h; T1/2,5. 72 h,5. 94 h,6. 78 h,3. 78 h; MRT_(0-∞),10. 30 h,9. 61 h,12. 30 h,4. 89 h; CL/F,7. 59 m L·kg-1·h~(-1),13. 88 m L·kg-1·h~(-1),7. 28 m L·kg-1·h~(-1),5. 52 m L·kg-1·h~(-1). Conclusions Multiple peak phenomenon can be observed in the plasma SQV profiles. Morin can significantly reduce the SQV oral bioavailability and affect SQV PK profiles while acetyl-resveratrol cannot significantly affect the SQV oral bioavailability and SQV PK profiles in rats.
引文
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[11]Buchanan C M,Buchanan N L,Edgar K J,et al.Pharmacokinetics of saquinavir after intravenous and oral dosing of saquinavir:hydroxybutenyl-beta-cyclodextrin formulations[J].Biomacromolecules,2008,9(1):305-13.
[12]Sahu K,Siddiqui A A,Shaharyar M,et al.Pharmacokinetic interaction between febuxostat and morin in rats[J].Expert Opin Drug Metab Toxicol,2014,10(3):307-12.
[13]Zhang S,Sagawa K,Arnold R D,et al.Interactions between the flavonoid biochanin A and P-glycoprotein substrates in rats:in vitro and in vivo[J].J Pharm Sci,2010,99(1):430-41.
[14]An G,Morris M E.Effects of the isoflavonoid biochanin A on the transport of mitoxantrone in vitro and in vivo[J].Biopharm Drug Dispos,2010,31(5-6):340-50.
[15]Chow H H,Garland L L,Hsu C H,et al.Resveratrol modulates drug-and carcinogen-metabolizing enzymes in a healthy volunteer study[J].Cancer Prev Res(Phila),2010,3(9):1168-75.
[16]Davies N M,Takemoto J K,Brocks D R,et al.Multiple peaking phenomena in pharmacokinetic disposition[J].Clin Pharmacokinet,2010,49(6):351-77.
[2]Mouly S J,Paine M F,Watkins P B.Contributions of CYP3A4,P-glycoprotein,and serum protein binding to the intestinal firstpass extraction of saquinavir[J].J Pharmacol Exp Ther,2004,308(3):941-8.
[3]Usansky H H,Hu P,Sinko P J.Differential roles of P-glycoprotein,multidrug resistance-associated protein 2,and CYP3A on saquinavir oral absorption in Sprague-Dawley rats[J].Drug Metab Dispos,2008,36(5):863-9.
[4]王玉璘,王少峡,郭虹,等.血脑屏障中P-糖蛋白的调节机制[J].中国药理学通报,2011,27(9):1196-200.[4]Wang Y L,Wang S X,Guo H,et al.Regulatory mechanisms of P-glycoprotein at the blood-brain barrier[J].Chin Pharmacol Bull,2011,27(9):1196-200.
[5]陈前昭,曾于桦,邵英,等.白藜芦醇抑制人结肠癌细胞增殖与p38 MAPK的关系研究[J].中国药理学通报,2016,32(8):1100-4.[5]Chen Q Z,Zeng Y Y,Shao Y,et al.Anti-proliferation effect of resveratrol and p38 MAPK in human colon cancer cells[J].Chin Pharmacol Bull,2016,32(8):1100-4.
[6]Choi B C,Choi J S,Han H K.Altered pharmacokinetics of paclitaxel by the concomitant use of morin in rats[J].Int J Pharm,2006,323(1-2):81-5.
[7]Li X,Yun J K,Choi J S.Effects of morin on the pharmacokinetics of etoposide in rats[J].Biopharm Drug Dispos,2007,28(3):151-6.
[8]Choi J S,Choi B C,Kang K W.Effect of resveratrol on the pharmacokinetics of oral and intravenous nicardipine in rats:possible role of P-glycoprotein inhibition by resveratrol[J].Pharmazie,2009,64(1):49-52.
[9]李佳朋,韦忠娜,刘阳,等.体外研究黄酮类和芪类化合物对血脑屏障P-糖蛋白外排沙奎那韦的影响[J].中国临床药理学杂志,2016,32(23):2187-90.[9]Li J P,Wei Z N,Liu Y,et al.Effects of several flavonoids and stilbenes on P-glycoprotein mediated efflux of saquinavir on bloodbrain barrier in vitro[J].Chin J Clin Pharmacol,2016,32(23):2187-90.
[10]Nakagami T,Yasui-Furukori N,Saito M,et al.Effect of verapamil on pharmacokinetics and pharmacodynamics of risperidone:in vivo evidence of involvement of P-glycoprotein in risperidone disposition[J].Clin Pharmacol Ther,2005,78(1):43-51.
[11]Buchanan C M,Buchanan N L,Edgar K J,et al.Pharmacokinetics of saquinavir after intravenous and oral dosing of saquinavir:hydroxybutenyl-beta-cyclodextrin formulations[J].Biomacromolecules,2008,9(1):305-13.
[12]Sahu K,Siddiqui A A,Shaharyar M,et al.Pharmacokinetic interaction between febuxostat and morin in rats[J].Expert Opin Drug Metab Toxicol,2014,10(3):307-12.
[13]Zhang S,Sagawa K,Arnold R D,et al.Interactions between the flavonoid biochanin A and P-glycoprotein substrates in rats:in vitro and in vivo[J].J Pharm Sci,2010,99(1):430-41.
[14]An G,Morris M E.Effects of the isoflavonoid biochanin A on the transport of mitoxantrone in vitro and in vivo[J].Biopharm Drug Dispos,2010,31(5-6):340-50.
[15]Chow H H,Garland L L,Hsu C H,et al.Resveratrol modulates drug-and carcinogen-metabolizing enzymes in a healthy volunteer study[J].Cancer Prev Res(Phila),2010,3(9):1168-75.
[16]Davies N M,Takemoto J K,Brocks D R,et al.Multiple peaking phenomena in pharmacokinetic disposition[J].Clin Pharmacokinet,2010,49(6):351-77.