盐酸小檗碱对大鼠体内他克莫司药动学的影响
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摘要
目的:研究盐酸小檗碱单次、多次给药对大鼠体内他克莫司药动学的影响,为两者联合用药提供参考。方法:将30只大鼠随机分为5组,每组6只,第1组大鼠单次灌胃他克莫司;第2组大鼠每日灌胃他克莫司2次,连续给药1周;第3组大鼠先单次灌胃盐酸小檗碱,5 min后单次灌胃他克莫司;第4组大鼠先每日灌胃他克莫司2次,连续给药1周,第8天时先灌胃盐酸小檗碱5 min后再灌胃他克莫司1次;第5组大鼠每日灌胃盐酸小檗碱2次,每次间隔5 min后相应灌胃他克莫司1次,连续给药8 d。盐酸小檗碱给药剂量均为200 mg/kg,他克莫司给药剂量均为0.945 mg/kg。末次灌胃他克莫司后0、5、15、30 min和1、2、3、4、6、8、12 h,分别从各组大鼠的眼眶后静脉丛取血约0.3 m L,采用液相色谱-串联质谱法(LC-MS/MS)测定大鼠全血中他克莫司的浓度,应用DAS2.0软件进行药动学研究。结果:与第1组比较,第3组大鼠体内的他克莫司药动学参数AUC_(0-12) h、AUC0-∞和MRT0-12 h显著降低(P<0.05),第4组大鼠体内他克莫司所有药动学参数差异均无统计学意义(P>0.05);与第2组比较,第4组大鼠体内他克莫司药动学参数AUC_(0-12) h显著降低、CLz显著升高(P<0.05),第5组大鼠体内他克莫司所有药动学参数差异均无统计学意义(P>0.05)。结论:单次、多次灌胃盐酸小檗碱均对大鼠体内他克莫司的药动学有影响,表现在血药浓度有下降的趋势,需谨慎联用。
OBJECTIVE:To study the effects of berberine hydrochloride on the pharmacokinetics of tacrolimus in rats after single or multiple administration,and to provide reference for clinical combination therapy. METHODS:30 rats were randomly divided into 5 groups,with 6 rats in each group:group one was treated with single administration of tacrolimus;group two was treated with tacrolimus intragastrically,twice a day,for consecutive 1 week;group three was treated with single administration of berberine hydrochloride, 5 min later given single administration of tacrolimus; group four was treated with tacrolimus intragastrically,twice a day,for consecutive 1 week,and then given tacrolimus intragastrically once 5 min after intragastric administration of berberine hydrochloride on the 8 th day;group five was treated with berberine hydrochloride intragastrically,twice a day,and given tacrolimus intragastrically every 5 min,for consecutive 8 d. The doses of berberine hydrochloride and tacrolimus were 200 mg/kg and 0.945 mg/kg. The blood samples 0.3 m L were collected from posterior orbital venous plexus of rats 0,5,15,30 min and 1,2,3,4,6,8,12 h after last intragastric administration of tacrolimus. The concentration of tacrolimus in rat whole blood was determined by LC-MS/MS. DAS 2.0 software was used for pharmacokinetic study. RESULTS:Compared with group one,the pharmacokinetic parameters AUC_(0-12) h,AUC0-∞and MRT0-12 hof tacrolimus in rats were decreased significantly in group three(P<0.05),while there was no statistical significance in all pharmacokinetic parameters of tacrolimus in group four(P>0.05).Compared with group two,AUC_(0-12) hof tacrolimus was decreased significantly while CLz was increased significantly in group four(P<0.05);there was no statistical significance in all pharmacokinetic parameters of tacrolimus in group five(P>0.05).CONCLUSIONS: Single and multiple intragastric administration of berberine hydrochloride has a certain effect on the pharmacokinetics of tacrolimus in rats,it shows that there is a downward trend in blood drug concentration and needs to be used with caution.
OBJECTIVE:To study the effects of berberine hydrochloride on the pharmacokinetics of tacrolimus in rats after single or multiple administration,and to provide reference for clinical combination therapy. METHODS:30 rats were randomly divided into 5 groups,with 6 rats in each group:group one was treated with single administration of tacrolimus;group two was treated with tacrolimus intragastrically,twice a day,for consecutive 1 week;group three was treated with single administration of berberine hydrochloride, 5 min later given single administration of tacrolimus; group four was treated with tacrolimus intragastrically,twice a day,for consecutive 1 week,and then given tacrolimus intragastrically once 5 min after intragastric administration of berberine hydrochloride on the 8 th day;group five was treated with berberine hydrochloride intragastrically,twice a day,and given tacrolimus intragastrically every 5 min,for consecutive 8 d. The doses of berberine hydrochloride and tacrolimus were 200 mg/kg and 0.945 mg/kg. The blood samples 0.3 m L were collected from posterior orbital venous plexus of rats 0,5,15,30 min and 1,2,3,4,6,8,12 h after last intragastric administration of tacrolimus. The concentration of tacrolimus in rat whole blood was determined by LC-MS/MS. DAS 2.0 software was used for pharmacokinetic study. RESULTS:Compared with group one,the pharmacokinetic parameters AUC_(0-12) h,AUC0-∞and MRT0-12 hof tacrolimus in rats were decreased significantly in group three(P<0.05),while there was no statistical significance in all pharmacokinetic parameters of tacrolimus in group four(P>0.05).Compared with group two,AUC_(0-12) hof tacrolimus was decreased significantly while CLz was increased significantly in group four(P<0.05);there was no statistical significance in all pharmacokinetic parameters of tacrolimus in group five(P>0.05).CONCLUSIONS: Single and multiple intragastric administration of berberine hydrochloride has a certain effect on the pharmacokinetics of tacrolimus in rats,it shows that there is a downward trend in blood drug concentration and needs to be used with caution.
引文
[1]STAATZ CE,TETT SE.Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation[J].Clin Pharmacokinet,2004,43(10):623-653.
[2]PATEL N,COOK A,GREENHALGH E,et al.Overview of extended release tacrolimus in solid organ transplantation[J].World J Transplant,2016,6(1):144-154.
[3]李晖,柴煊,李新芳,等.黄连素临床新用途及其不良反应[J].武警医学,2008,19(7):661-663.
[4]GUO Y,CHEN Y,TAN ZR,et al.Repeated administration of berberine inhibits cytochromes P450in humans[J].Eur J Clin Pharmacol,2012,68(2):213-217.
[5]QIU W,JIANG XH,LIU CX,et al.Effect of berberine on the pharmacokinetics of substrates of CYP3A and P-gp[J].Phytother Res,2009,23(11):1553-1558.
[6]CUI HM,ZHANG QY,WANG JL,et al.In vitro studies of berberine metabolism and its effect of enzyme induction on HepG2 cells[J].J Ethnopharmacol,2014,158(1):388-396.
[7]WU X,LI Q,XIN H,et al.Effects of berberine on the blood concentration of cyclosporin A in renal transplanted recipients:clinical and pharmacokinetic study[J].Eur JClin Pharmacol,2005,61(8):567-572.
[8]吴笑春,李罄,辛华雯,等.黄连素与环孢素A合用的药物经济学研究[J].华南国防医学杂志,2002,16(1):8-11.
[9]史天陆,孙言才,沈爱宗,等.他克莫司临床不良反应与防治[J].中国医院用药评价与分析,2009,9(1):67-69.
[10]ABD EA,GHAREEB DA,SARHAN EE,et al.In vitro biological assessment of Berberis vulgaris and its active constituent,berberine:antioxidants,anti-acetylcholinesterase,anti-diabetic and anticancer effects[J].BMC Complement Altern Med,2013,13(2):218-220.
[11]KONG W,WEIJ,ABIDI P,et al.Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins[J].Nat Med,2004,10(12):1344-1351.
[12]HOU Q,HAN W,FU X.Pharmacokinetic interaction between tacrolimus and berberine in a child with idiopathic nephrotic syndrome[J].Eur J Clin Pharmacol,2013,69(10):1861-1862.
[13]蔡明志,陈凯,范星,等.盐酸小檗碱引起他克莫司血药浓度升高1例分析[J].实用医药杂志,2014,31(2):156-157.
[14]逄晓云,沈金芳.盐酸小檗碱致他克莫司血药浓度升高1例[J].中国药物警戒,2012,2(10):640-641.
[15]冯格,翟健秀,陈万生,等.五酯胶囊/五味子酯甲和环磷酰胺联合给药对大鼠体内环磷酰胺药动学的影响研究[J].中国药房,2018,29(3):307-311.
[16]常伟宇,辛华雯,唐霞,等.盐酸小檗碱对大鼠体内咪达唑仑及其代谢产物药动学的影响[J].医药导报,2016,35(4):331-336.
[17]辛华雯,吴笑春,李罄,等.盐酸小檗碱及其与环孢素A合用对大鼠肝脏和小肠CYP3A2表达影响[J].中国药学杂志,2005,40(5):353-356.
[18]STAATZ CE,TETT SE.Clinical pharmacokinetics of once-daily tacrolimus in solid-organ transplant patients[J].Clin Pharmacokinet,2015,54(10):993-1025.
[19]VALBUENA H,SHIPKOVA M,KLIESCHS M,et al.Comparing the effect of isotopically labeled or structural analog internal standards on the performance of a LC-MS/MS method to determine ciclosporin A,everolimus,sirolimus and tacrolimus in whole blood[J].Clin Chem Lab Med,2016,54(3):437-446.
[20]PARK JS,CHO HR,KANG MJ,et al.A rapid and sensitive method to determine tacrolimus in rat whole blood using liquid-liquid extraction with mild temperature ultrasonication and LC-MS/MS[J].Arch Pharm Res,2016,39(1):73-82.
[21]RAMAKRISHNA NV,VISHWOTTAM KN,PURAN S,et al.Liquid chromatography-negative ion electrospray tandem mass spectrometry method for the quantification of tacrolimus in human plasma and its bioanalytical applications[J].J Chromatogr B Analyt Technol Biomed Life Sci,2004,805(1):13-20.
[22]SHIPKOVA M,SVINAROV D.LC-MS/MS as a tool for TDM services:where are we?[J].Clin Biochem,2016,49(13/14):1009-1023.
[23]VAN EECKHAUT A,LANCKMANS K,SARRE S,et al.Validation of bioanalytical LC-MS/MS assays:evaluation of matrix effects[J].J Chromatogr B Analyt Technol Biomed Life Sci,2009,877(23):2198-2207.
[24]BODNAR-BRONIARCZYK M,PAWINSKI T,KUICKIPK.Isotope-labeled versus analog internal standard in LC-MS/MS method for tacrolimus determination in human whole blood samples-A compensation of matrix effects[J].J Chromatogr B Analyt Technol Biomed Life Sci,2019.DOI:10.1016/j.jchromb.2018.11.026.
[25]薛新平.五酯片对细胞色素P4503A和P-糖蛋白活性影响的研究[D].广州:中山大学,2010.
[2]PATEL N,COOK A,GREENHALGH E,et al.Overview of extended release tacrolimus in solid organ transplantation[J].World J Transplant,2016,6(1):144-154.
[3]李晖,柴煊,李新芳,等.黄连素临床新用途及其不良反应[J].武警医学,2008,19(7):661-663.
[4]GUO Y,CHEN Y,TAN ZR,et al.Repeated administration of berberine inhibits cytochromes P450in humans[J].Eur J Clin Pharmacol,2012,68(2):213-217.
[5]QIU W,JIANG XH,LIU CX,et al.Effect of berberine on the pharmacokinetics of substrates of CYP3A and P-gp[J].Phytother Res,2009,23(11):1553-1558.
[6]CUI HM,ZHANG QY,WANG JL,et al.In vitro studies of berberine metabolism and its effect of enzyme induction on HepG2 cells[J].J Ethnopharmacol,2014,158(1):388-396.
[7]WU X,LI Q,XIN H,et al.Effects of berberine on the blood concentration of cyclosporin A in renal transplanted recipients:clinical and pharmacokinetic study[J].Eur JClin Pharmacol,2005,61(8):567-572.
[8]吴笑春,李罄,辛华雯,等.黄连素与环孢素A合用的药物经济学研究[J].华南国防医学杂志,2002,16(1):8-11.
[9]史天陆,孙言才,沈爱宗,等.他克莫司临床不良反应与防治[J].中国医院用药评价与分析,2009,9(1):67-69.
[10]ABD EA,GHAREEB DA,SARHAN EE,et al.In vitro biological assessment of Berberis vulgaris and its active constituent,berberine:antioxidants,anti-acetylcholinesterase,anti-diabetic and anticancer effects[J].BMC Complement Altern Med,2013,13(2):218-220.
[11]KONG W,WEIJ,ABIDI P,et al.Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins[J].Nat Med,2004,10(12):1344-1351.
[12]HOU Q,HAN W,FU X.Pharmacokinetic interaction between tacrolimus and berberine in a child with idiopathic nephrotic syndrome[J].Eur J Clin Pharmacol,2013,69(10):1861-1862.
[13]蔡明志,陈凯,范星,等.盐酸小檗碱引起他克莫司血药浓度升高1例分析[J].实用医药杂志,2014,31(2):156-157.
[14]逄晓云,沈金芳.盐酸小檗碱致他克莫司血药浓度升高1例[J].中国药物警戒,2012,2(10):640-641.
[15]冯格,翟健秀,陈万生,等.五酯胶囊/五味子酯甲和环磷酰胺联合给药对大鼠体内环磷酰胺药动学的影响研究[J].中国药房,2018,29(3):307-311.
[16]常伟宇,辛华雯,唐霞,等.盐酸小檗碱对大鼠体内咪达唑仑及其代谢产物药动学的影响[J].医药导报,2016,35(4):331-336.
[17]辛华雯,吴笑春,李罄,等.盐酸小檗碱及其与环孢素A合用对大鼠肝脏和小肠CYP3A2表达影响[J].中国药学杂志,2005,40(5):353-356.
[18]STAATZ CE,TETT SE.Clinical pharmacokinetics of once-daily tacrolimus in solid-organ transplant patients[J].Clin Pharmacokinet,2015,54(10):993-1025.
[19]VALBUENA H,SHIPKOVA M,KLIESCHS M,et al.Comparing the effect of isotopically labeled or structural analog internal standards on the performance of a LC-MS/MS method to determine ciclosporin A,everolimus,sirolimus and tacrolimus in whole blood[J].Clin Chem Lab Med,2016,54(3):437-446.
[20]PARK JS,CHO HR,KANG MJ,et al.A rapid and sensitive method to determine tacrolimus in rat whole blood using liquid-liquid extraction with mild temperature ultrasonication and LC-MS/MS[J].Arch Pharm Res,2016,39(1):73-82.
[21]RAMAKRISHNA NV,VISHWOTTAM KN,PURAN S,et al.Liquid chromatography-negative ion electrospray tandem mass spectrometry method for the quantification of tacrolimus in human plasma and its bioanalytical applications[J].J Chromatogr B Analyt Technol Biomed Life Sci,2004,805(1):13-20.
[22]SHIPKOVA M,SVINAROV D.LC-MS/MS as a tool for TDM services:where are we?[J].Clin Biochem,2016,49(13/14):1009-1023.
[23]VAN EECKHAUT A,LANCKMANS K,SARRE S,et al.Validation of bioanalytical LC-MS/MS assays:evaluation of matrix effects[J].J Chromatogr B Analyt Technol Biomed Life Sci,2009,877(23):2198-2207.
[24]BODNAR-BRONIARCZYK M,PAWINSKI T,KUICKIPK.Isotope-labeled versus analog internal standard in LC-MS/MS method for tacrolimus determination in human whole blood samples-A compensation of matrix effects[J].J Chromatogr B Analyt Technol Biomed Life Sci,2019.DOI:10.1016/j.jchromb.2018.11.026.
[25]薛新平.五酯片对细胞色素P4503A和P-糖蛋白活性影响的研究[D].广州:中山大学,2010.