辛伐他汀和利伐沙班联合给药对大鼠体内利伐沙班药动学的影响
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摘要
目的:研究辛伐他汀和利伐沙班联合给药对大鼠体内利伐沙班药动学的影响。方法:将30只大鼠随机分为利伐沙班组(灌胃生理盐水+利伐沙班2.6 mg/kg)和辛伐他汀+利伐沙班组(灌胃辛伐他汀5.3 mg/kg+利伐沙班2.6 mg/kg),每组15只。各组大鼠先连续灌胃生理盐水/辛伐他汀5 d,每天给药1次,第6天再灌胃利伐沙班+生理盐水/辛伐他汀1次,分别于给药前和末次给药后0.25、0.5、0.75、1、1.5、2、4、8、12、24 h自眼内眦取血0.5 m L,采用液相色谱-串联质谱(LC-MS/MS)法测定大鼠血浆中利伐沙班的质量浓度,绘制药-时曲线,并用DAS 2.1.1软件拟合药动学参数。结果:利伐沙班组和辛伐他汀+利伐沙班组大鼠血浆中利伐沙班的AUC0-24 h分别为(2 599.86±791.82)、(2 777.74±989.25)ng·h/mL,AUC_(0-∞)分别为(3 053.28±1 116.06)、(3 396.78±1 409.80)ng·h/mL,t1/2分别为(8.06±3.52)、(9.25±4.18)h,t_(max)分别为(0.65±0.28)h、(0.60±0.13)h,CLZ分别为(0.95±0.32)、(0.88±0.34)L/(h·kg),V_d分别为(10.37±4.43)、(11.07±4.48)L/kg,c_(max)分别为(424.93±145.30)、(507.15±132.40)ng/mL;与利伐沙班组比较,辛伐他汀+利伐沙班组AUC_(0-24 h)、AUC_(0-∞)、t_(1/2)、V_d、c_(max)分别增加了6.40%、10.11%、12.86%、6.32%、16.21%,t_(max)、CLZ分别降低了8.33%、7.95%,但差异无统计学意义(P>0.05)。结论:辛伐他汀(5.3 mg/kg)与利伐沙班(2.6 mg/kg)联用后,利伐沙班在大鼠体内的药动学参数无显著性变化。
OBJECTIVE:To study the effects of simvastatin combined with rivaroxaban on pharmacokinetics of rivaroxaban in rats. METHODS: Thirty rats were randomly divided into rivaroxaban group(intragastric administration of normal saline +rivaroxaban 2.6 mg/kg),simvastatin + rivaroxaban group(intragastric administration of simvastatin 5.3 mg/kg + rivaroxaban 2.6 mg/kg),with 15 rats in each group. The rats were given normal saline/simvastatin intragastrically for 5 d,once a day,and then given intragastric administration of rivaroxaban+normal saline/simvastain once. The blood samples were collected from orbital cavity of rats before medication and 0.25,0.5,0.75,1,1.5,2,4,8,12,24 h after medication. The plasma concentration of rivaroxaban was determined by LC-MS/MS. Plasma concentration-time curves were drawn,and the pharmacokinetic parameters were fitted by DAS 2.1.1 software. RESULTS:The pharmacokinetic parameters of rivaroxaban group and simvastatin+rivaroxaban group in rats included that AUC0-24 hwere(2 599.86±791.82)and(2 777.74±989.25)ng·h/mL;AUC_(0-∞)were(3 053.28±116.06)ng·h/mL and(3 396.78±1 409.80)ng·h/mL;t1/2 were(8.06±3.52)h and(9.25±4.18)h;t_(max)were(0.65±0.28)h and(0.60±0.13)h;CLZwere(0.95±0.32)L/(h·kg)and(0.88±0.34)L/(h·kg);V_d were(10.37±4.43)L/kg and(11.07±4.48)L/kg;c_(max)were(424.93±145.30)ng/m L and(507.15±132.40)ng/m L. Compared with rivaroxaban group,AUC_(0-24) h,AUC_(0-∞),t_(1/2),V_d and c_(max)of simvastatin+rivaroxaban group increased by 6.40%,10.11%,12.86%,6.32%,16.21%;t_(max)and CLZdecreased by 8.33% and 7.95%. There was no significant difference(P>0.05). CONCLUSIONS: There is no significant change in pharmacokinetic parameters of rivaroxaban in rats after combination of simvastatin(5.3 mg/kg)and rivaroxaban(2.6 mg/kg).
OBJECTIVE:To study the effects of simvastatin combined with rivaroxaban on pharmacokinetics of rivaroxaban in rats. METHODS: Thirty rats were randomly divided into rivaroxaban group(intragastric administration of normal saline +rivaroxaban 2.6 mg/kg),simvastatin + rivaroxaban group(intragastric administration of simvastatin 5.3 mg/kg + rivaroxaban 2.6 mg/kg),with 15 rats in each group. The rats were given normal saline/simvastatin intragastrically for 5 d,once a day,and then given intragastric administration of rivaroxaban+normal saline/simvastain once. The blood samples were collected from orbital cavity of rats before medication and 0.25,0.5,0.75,1,1.5,2,4,8,12,24 h after medication. The plasma concentration of rivaroxaban was determined by LC-MS/MS. Plasma concentration-time curves were drawn,and the pharmacokinetic parameters were fitted by DAS 2.1.1 software. RESULTS:The pharmacokinetic parameters of rivaroxaban group and simvastatin+rivaroxaban group in rats included that AUC0-24 hwere(2 599.86±791.82)and(2 777.74±989.25)ng·h/mL;AUC_(0-∞)were(3 053.28±116.06)ng·h/mL and(3 396.78±1 409.80)ng·h/mL;t1/2 were(8.06±3.52)h and(9.25±4.18)h;t_(max)were(0.65±0.28)h and(0.60±0.13)h;CLZwere(0.95±0.32)L/(h·kg)and(0.88±0.34)L/(h·kg);V_d were(10.37±4.43)L/kg and(11.07±4.48)L/kg;c_(max)were(424.93±145.30)ng/m L and(507.15±132.40)ng/m L. Compared with rivaroxaban group,AUC_(0-24) h,AUC_(0-∞),t_(1/2),V_d and c_(max)of simvastatin+rivaroxaban group increased by 6.40%,10.11%,12.86%,6.32%,16.21%;t_(max)and CLZdecreased by 8.33% and 7.95%. There was no significant difference(P>0.05). CONCLUSIONS: There is no significant change in pharmacokinetic parameters of rivaroxaban in rats after combination of simvastatin(5.3 mg/kg)and rivaroxaban(2.6 mg/kg).
引文
[1]朱愿超,赵紫楠,梁良,等.北京医院786例患者利伐沙班的应用分析[J].临床药物治疗杂志,2018,16(4):58-61.
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[12]王清理,王晓慧,卫永丽.某三甲医院心内科CYP3A4抑制剂与阿托伐他汀或辛伐他汀联用情况分析[J].中国药房,2015,26(33):4634-4637.
[13] BELLOSTA S,PAOLETTI R,CORSINI A. Safety of statins:focus on clinical pharmacokinetics and drug interactions[J]. Circulation,2004.DOI:10.1161/01.CIR.000013-1519.15067.1f.
[14] KUBITZA D,BECKA M,ROTH A,et al. Absence of clinically relevant interactions between rivaroxaban an oral,direct factorⅩa inhibitor and digoxin or atorvastatin in healthy subjects[J]. J Int Med Res,2012,40(5):1688-1707.
[15] VRANCKX P,VALGIMIGLI M,HEIDBUCHEL H. The significance of drug-drug and drug-food interactions of oral anticoagulation[J]. Arrhythm Electrophysiol Rev,2018,7(1):55-61.
[16] MUECK W,STAMPFUSS J,KUBITZA D,et al. Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban[J]. Clin Pharmacokinet,2014,53(1):1-16.
[17] WILLMANN S,ZHANG L,FREDE M,et al. Integrated population pharmacokinetic analysis of rivaroxaban across multiple patient populations[J]. CPT Pharmacometrics Syst Pharmacol,2018,7(5):309-320.
[18] VICKERS S,DUNCAN CA,VYAS KP,et al. In vitro and in vivo biotransformation of simvastatin,an inhibitor of HMG CoA reductase[J]. Drug Metab Dispos,1990,18(4):476-483.
[2]宫明莲.分析利伐沙班治疗房颤合并稳定性冠心病患者的临床疗效[J].中国现代药物应用,2018,12(1):92-93.
[3]刘晓,崔一民.新型抗凝血药物:利伐沙班[J].中国药房,2010,21(1):83-86.
[4]李焰生.预防心源性卒中的新型抗凝药物[J].中国新药杂志,2011,20(11):981-984.
[5]李楠,赵庆春,党大胜.利伐沙班与传统抗凝方案对冠脉事件影响Meta分析[J].临床军医杂志,2018,46(3):258-262.
[6]付鸿江,裴效瑞.利伐沙班不同疗程防治全髋关节置换术后深静脉血栓的效果及安全性观察[J].中国药房,2017,28(11):1506-1509.
[7]邢贞武,余德涛,邢祯全,等.利伐沙班与低分子肝素钙预防全髋关节置换术后深静脉血栓的效果比较[J].中国药房,2017,28(23):3247-3250.
[8]车志,宋华锋,邹月柳,等.利伐沙班与华法林治疗中国人群血栓性疾病的疗效及安全性对比的Meta分析[J].循证医学,2018,18(1):48-54.
[9] HUANG HY,LIN SY,CHENG SH,et al. Effectiveness and safety of different rivaroxaban dosage regimens in patients with non-valvular atrial fibrillation:a nationwide,population-based cohort study[J]. Sci Rep,2018,8(1):3451-3459.
[10]许坤,赵弘卿,冯金萍,等.低分子肝素钙和利伐沙班联合阿托伐他汀对急性肺栓塞患者相关指标的影响[J].中国药房,2017,28(21):2940-2943.
[11]曾惠权,霍炽荣,潘春予.阿托伐他汀在急性肺动脉栓塞患者中的应用[J].中国医药指南,2015,13(4):126-126.
[12]王清理,王晓慧,卫永丽.某三甲医院心内科CYP3A4抑制剂与阿托伐他汀或辛伐他汀联用情况分析[J].中国药房,2015,26(33):4634-4637.
[13] BELLOSTA S,PAOLETTI R,CORSINI A. Safety of statins:focus on clinical pharmacokinetics and drug interactions[J]. Circulation,2004.DOI:10.1161/01.CIR.000013-1519.15067.1f.
[14] KUBITZA D,BECKA M,ROTH A,et al. Absence of clinically relevant interactions between rivaroxaban an oral,direct factorⅩa inhibitor and digoxin or atorvastatin in healthy subjects[J]. J Int Med Res,2012,40(5):1688-1707.
[15] VRANCKX P,VALGIMIGLI M,HEIDBUCHEL H. The significance of drug-drug and drug-food interactions of oral anticoagulation[J]. Arrhythm Electrophysiol Rev,2018,7(1):55-61.
[16] MUECK W,STAMPFUSS J,KUBITZA D,et al. Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban[J]. Clin Pharmacokinet,2014,53(1):1-16.
[17] WILLMANN S,ZHANG L,FREDE M,et al. Integrated population pharmacokinetic analysis of rivaroxaban across multiple patient populations[J]. CPT Pharmacometrics Syst Pharmacol,2018,7(5):309-320.
[18] VICKERS S,DUNCAN CA,VYAS KP,et al. In vitro and in vivo biotransformation of simvastatin,an inhibitor of HMG CoA reductase[J]. Drug Metab Dispos,1990,18(4):476-483.
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