舒芬太尼与右美托咪啶联合用药在大鼠中的药动学及其镇静作用
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摘要
目的研究舒芬太尼(SFTN)与右美托咪啶(DEM)联合用药大鼠中的血浆动力学、靶器官分布及其镇静作用和呼吸抑制毒性,分析两药的药-药相互作用。方法雄性SD大鼠分别iv给予SFTN 20.0μg·kg~(-1),DEM 25.2μg·kg~(-1)或SFTN 20.0μg·kg~(-1)+DEM 25.2μg·kg~(-1),于给药后2,5,15,30 min和1,2,4,6和8 h采血,用本研究建立的液相色谱-质谱联用(LC-MS/MS)定量检测方法测定血浆中SFTN和DEM浓度;于给药后5,15,30,60和120 min取血和脑组织样品,同法测定血浆和脑组织中SFTN和DEM浓度。采用WinNonlin 7.0软件拟合并获得药动学参数。采用清醒大鼠肺功能仪考察两药联合应用后呼吸抑制作用,通过观察翻正反射消失(LORR)持续时间考察其中枢镇静作用。结果建立并验证了定量检测血浆样品SFTN和DEM浓度的LC-MS/MS方法。大鼠给药后,SFTN组SFTN的血浆峰浓度(C_(max)),消除半衰期(t_(1/2))和血浆清除率(Cl)分别为(22.2±2.6)μg·L~(-1),(2.13±0.69)h和(2288±446)mL·h~(-1)·kg~(-1),SFTN+DEM组SFTN分别为(15.9±9.4)μg·L~(-1),(1.22±0.13)h和(3565±743)m L·h~(-1)·kg~(-1);DEM组DEM分别为(14.0±8.9)μg·L~(-1),(1.21±0.15)h和(4235±752)mL·h~(-1)·kg~(-1),SFTN+DEM组DEM分别为(9.4±3.5)μg·L~(-1),(1.08±0.26)h和(4796±744)mL·h~(-1)·kg~(-1)。SFTN+DEM组SFTN的脑/血浆C_(max)比值为0.49,是SFTN组(0.45)的1.3倍;SFTN+DEM组DEM的脑/血浆C_(max)比值为16.9,是DEM组(1.42)的12倍。SFTN,DEM和SFTN+DEM组大鼠LORR持续时间分别为37±13,41±5和(104±24)min,SFTN+DEM组LORR持续时间相比SFTN和DEM组显著延长(P<0.01)。SFTN+DEM组大鼠呼吸功能被抑制程度与SFTN组相比无明显加重,但抑制时间有一定延长(P<0.05,P<0.01)。结论 SFTN与DEM联合用药存在一定的药-药相互作用,可能通过增加脑组织DEM暴露水平而延长镇静作用和呼吸抑制作用的持续时间,临床应用时应关注两药联合应用可能导致的药效或副作用的协同作用。
OBJECTIVE To evaluate plasma pharmacokinetics, distribution of target organs, sedative effect and respiratory depression of sufentanil(SFTN), and dexmedetomidine(DEM) in rats, and to explore the potential drug-drug interactions between the two drugs. METHODS Rats were intravenously injected with SFTN 20.0 μg·kg~(-1), DEM 25.2 μg·kg~(-1) and SFTN+DEM(SFTN 20.0 μg·kg~(-1), DEM 25.2 μg·kg~(-1)),respectively. Plasma samples were taken at different time points(2, 5, 15, 30 min and 1, 2, 4, 6, 8 h) to determine the concentrations of SFTN and DEM using the liquid chromatography-mass spectrometry(LC-MS/MS) quantitative method established in this study. The same method was used to determine the concentrations of SFTN and DEM in plasma and brain samples taken at different time points(5, 15,30, 60 and 120 min). Pharmacokinetic parameters were obtained by noncompartmental analysis performed using Phoenix WinNonlin 7.0(Pharsight, California). The duration of drug-induced loss of right reflex(LORR) and respiratory function were also measured using instrument monitoring. RESULTS An LC-MS/MS method for quantitative analysis of plasma SFTN and DEM was established and validated. The C_(max),t_(1/2), and Cl of SFTN in SFTN group were(22.2±2.6) ug·L~(-1),(2.13±0.69) h and(2288±446) mL·h~(-1)·kg~(-1),respectively, compared with(15.9±9.4) μg·L~(-1),(1.22±0.13) h and(3565±743) mL·h~(-1)·kg~(-1) in SFTN+DEM group. The C_(max), t_(1/2), and Cl of DEM in DEM group were(14.0±8.9) μg·L~(-1),(1.21±0.15) h and (4235±752) m L·h~(-1)·kg~(-1), compared with(9.4±3.5) μg·L~(-1),(1.08±0.26) h and (4796±744) mL·h~(-1)·kg~(-1) in SFTN+DEM group. The C_(max)ratio of SFTN in brain and plasma of SFTN+DEM group was 0.49, which was 1.3-fold that of SFTN group(0.45). The C_(max)ratio of DEM in brain and plasma of SFTN+DEM group was 16.9, which was 12-fold that of DEM group(1.42). The duration of LORR of SFTN, DEM,and SFTN+DEM groups was 370±13, 41±5 and(104±24) min, respectively, and that of SFTN+DEM group was more significantly extended than those in SFTN and DEM groups(P<0.01). Respiratory depression of SFTN+DEM group was not further aggravated compared with SFTN group, but the duration of inhibition was extended(P<0.05, P<0.01). CONCLUSION The combination of SFTN and DEM can cause drug-drug interactions, which may promote the sedation and prolong the respiratory depression by increasing the exposure level of DEM brain tissue. In clinical application, attention should be paid to the possible drug-drug interactions or adverse reactions caused by the combination of these two drugs.
OBJECTIVE To evaluate plasma pharmacokinetics, distribution of target organs, sedative effect and respiratory depression of sufentanil(SFTN), and dexmedetomidine(DEM) in rats, and to explore the potential drug-drug interactions between the two drugs. METHODS Rats were intravenously injected with SFTN 20.0 μg·kg~(-1), DEM 25.2 μg·kg~(-1) and SFTN+DEM(SFTN 20.0 μg·kg~(-1), DEM 25.2 μg·kg~(-1)),respectively. Plasma samples were taken at different time points(2, 5, 15, 30 min and 1, 2, 4, 6, 8 h) to determine the concentrations of SFTN and DEM using the liquid chromatography-mass spectrometry(LC-MS/MS) quantitative method established in this study. The same method was used to determine the concentrations of SFTN and DEM in plasma and brain samples taken at different time points(5, 15,30, 60 and 120 min). Pharmacokinetic parameters were obtained by noncompartmental analysis performed using Phoenix WinNonlin 7.0(Pharsight, California). The duration of drug-induced loss of right reflex(LORR) and respiratory function were also measured using instrument monitoring. RESULTS An LC-MS/MS method for quantitative analysis of plasma SFTN and DEM was established and validated. The C_(max),t_(1/2), and Cl of SFTN in SFTN group were(22.2±2.6) ug·L~(-1),(2.13±0.69) h and(2288±446) mL·h~(-1)·kg~(-1),respectively, compared with(15.9±9.4) μg·L~(-1),(1.22±0.13) h and(3565±743) mL·h~(-1)·kg~(-1) in SFTN+DEM group. The C_(max), t_(1/2), and Cl of DEM in DEM group were(14.0±8.9) μg·L~(-1),(1.21±0.15) h and (4235±752) m L·h~(-1)·kg~(-1), compared with(9.4±3.5) μg·L~(-1),(1.08±0.26) h and (4796±744) mL·h~(-1)·kg~(-1) in SFTN+DEM group. The C_(max)ratio of SFTN in brain and plasma of SFTN+DEM group was 0.49, which was 1.3-fold that of SFTN group(0.45). The C_(max)ratio of DEM in brain and plasma of SFTN+DEM group was 16.9, which was 12-fold that of DEM group(1.42). The duration of LORR of SFTN, DEM,and SFTN+DEM groups was 370±13, 41±5 and(104±24) min, respectively, and that of SFTN+DEM group was more significantly extended than those in SFTN and DEM groups(P<0.01). Respiratory depression of SFTN+DEM group was not further aggravated compared with SFTN group, but the duration of inhibition was extended(P<0.05, P<0.01). CONCLUSION The combination of SFTN and DEM can cause drug-drug interactions, which may promote the sedation and prolong the respiratory depression by increasing the exposure level of DEM brain tissue. In clinical application, attention should be paid to the possible drug-drug interactions or adverse reactions caused by the combination of these two drugs.
引文
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[17]Zhan L,Chen T,Wang J,Wang CS,Wang Q.Advances in peripheral opioid receptors[J].Chin J Pain Med(中国疼痛医学杂志),2013,19(5):289-292.
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[3]Hsu YW,Cortinez LI,Robertson KM,Keifer JC,Sum-Ping ST,Moretti EW,et al.Dexmedetomidine pharmacodynamics:partⅠ:crossover comparison of the respiratory effects of dexmedetomidine and remifentanil in healthy volunteers[J].Anesthesiology,2004,101(5):1066-1076.
[4]Dong CS,Lu Y,Zhang J,Sun P,Yu JM,Wu C,et al.The optimal dose of dexmedetomidine added to an sufentanil-based analgesic regimen for postoperative pain control in spine surgery:a probit analysis study[J/OL].Medicine(Baltimore),2016,95(39):e4776(2016-09-30).https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5265895/
[5]Qin M,Chen K,Liu T,Shen X.Dexmedetomidine in combination with sufentanil for postoperative analgesia after partial laryngectomy[J/OL].BMC Anesthesiol,2017,17(1):66(2017-05-25).https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5445400/
[6]Zhang XK,Chen QH,Wang WX,Hu Q.Evaluation of dexmedetomidine in combination with sufentanil or butorphanol for postoperative analgesia in patients undergoing laparoscopic resection of gastrointestinal tumors:a quasi-experimental trial[J/OL].Medicine(Baltimore),2016,95(50):e5604(2016-12-16).https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5268046/
[7]Su S,Ren C,Zhang H,Liu Z,Zhang Z.The opioidsparing effect of perioperative dexmedetomidine plus sufentanil infusion during neurosurgery:a retrospective study[J/OL].Front Pharmacol,2016,7:407(2016-10-26).https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5080288/
[8]Hitt JM,Corcoran T,Michienzi K,Creighton P,Heard C.An evaluation of intranasal sufentanil and dexmedetomidine for pediatric dental sedation[J].Pharmaceutics,2014,6(1):175-184.
[9]Nie Y,Liu Y,Luo Q,Huang S.Effect of dexmedetomidine combined with sufentanil for post-caesarean section intravenous analgesia:a randomised,placebocontrolled study[J].Eur J Anaesthesiol,2014,31(4):197-203.
[10]Yang LF,Pan P,Tan H,Jiang H.Clinical analysis of dexmedetomidine combined with sufentanil for intravenous analgesia after total hysterectomy[J].China Foreign Med Treat(中外医疗),2018,(13):124-126.
[11]Yu CC.Study on P-glycoprotein mediated bloodbrain penetration and central nervous system toxicity of fentanyl drugs(P蛋白介导的芬太尼类药物血脑屏障通透性及中枢毒性的研究)[D].Beijing:Academy of Military Medical Sciences(军事医学科学院),2018.
[12]Yu C,Yuan M,Yang H,Zhuang X,Li H.P-glycoprotein on blood-brain barrier plays a vital role in fentanyl brain exposure and respiratory toxicity in rats[J].Toxicol Sci,2018,164(1):353-362.
[13]Xu JG.Progress of postoperative pain management in adults[J].J Clin Anesthesiol(临床麻醉学杂志),2011,27(3):299-301.
[14]Li TK,Wang L,Sun YL,LV SG,Wang GS,Lu XH.Effect of dexmedetomidine on bispectral index and haemodynamics during propofol anesthesia recovery period[J].J Zhengzhou Univ(Med Sci)[郑州大学学报(医学版)],2015,50(1):107-109.
[15]Xu HF.Clinical application of opioid analgesics[J].Chin J Anesthesiol(中华麻醉学杂志),2001,21(10):599-602.
[16]Ye TH,Li DK.Anesthetic Pharmacology,Primary Physiology and Clinical Practice(麻醉药理学基础与临床)[M].Beijing:People′s Medical Publishing House(人民卫生出版社),2011,475-476.
[17]Zhan L,Chen T,Wang J,Wang CS,Wang Q.Advances in peripheral opioid receptors[J].Chin J Pain Med(中国疼痛医学杂志),2013,19(5):289-292.