This paper reports the development and validation of an assay for ifenprodil based on liquid chromatography–tandem mass spectrometry(LC–MS/MS)and its application to a pharmacokinetic study involving single and multi...This paper reports the development and validation of an assay for ifenprodil based on liquid chromatography–tandem mass spectrometry(LC–MS/MS)and its application to a pharmacokinetic study involving single and multiple intravenous infusions to healthy Chinese volunteers.After sample preparation of plasma by liquid–liquid extraction with ethyl acetate,the analyte and internal standard,urapidil,were separated by reversed phase chromatography in a run time of 4 min and detected by positive ion electrospray ionization followed by multiple reaction monitoring of the precursor-to-product ion transitions at m/z 326.2-308.1 for ifenprodil and m/z 388.4-205.3 for IS.The assay was linear in the concentration range 0.2–50.0 ng/mL with recovery 476.4%.In the pharmacokinetic study of single intravenous infusions of 5,10 and 15 mg ifenprodil,peak plasma concentrations and areas under the plasma concentration–time curve were both linearly related to dose.In the pharmacokinetic study of multiple once daily intravenous infusions of 10 mg ifenprodil for 7 days,pharmacokinetic parameters were similar to those after the single dose showing that ifenprodil does not accumulate on repeated administration.展开更多
目的：建立HPLC-MS法测定大鼠体内艾芬地尔的血药浓度,并研究酒石酸艾芬地尔在健康SD大鼠体内的药代动力学特征。方法：血浆样品碱化后采用乙酸乙酯液-液萃取处理,酮康唑为内标。采用C18色谱柱（5μm,4.6 mm×150mm）,以甲醇-p H 7...目的：建立HPLC-MS法测定大鼠体内艾芬地尔的血药浓度,并研究酒石酸艾芬地尔在健康SD大鼠体内的药代动力学特征。方法：血浆样品碱化后采用乙酸乙酯液-液萃取处理,酮康唑为内标。采用C18色谱柱（5μm,4.6 mm×150mm）,以甲醇-p H 7.20醋酸铵溶液为流动相,梯度洗脱（0-3 min,20%A→90%A,80%B→10%B）,流速0.6 m L·min^-1。质谱检测采用电喷雾（ESI）离子源,正离子模式,采用选择离子检测（SIM）方式检测,检测离子分别为m/z 326.3（艾芬地尔）、m/z 531.0（酮康唑）。选取健康SD大鼠[（250±20）g,雌雄各半],腹腔注射酒石酸艾芬地尔1 mg·kg-1后,采用建立的HPLC-MS法测定各个时间点（0、10、20、30、40、50、60、75、90、100、110、120、150、180、240、360 min,每个时间点6只）大鼠血浆中艾芬地尔的浓度,并计算其药代动力学参数。结果：艾芬地尔浓度在0.5-120μg·L^-1范围内,线性良好（r=0.9974）;日间、日内精密度RSD均小于10.5%,提取回收率均高于88%,专属性良好,血浆样品在本实验的条件下稳定,空白基质中的内源性物质不干扰待测组分和内标的测定。结论：本分析方法对血浆中艾芬地尔的检测具有专属性,且灵敏、可靠。酒石酸艾芬地尔经腹腔注射后在大鼠体内药动学模型为单室模型,其达峰浓度为113.79μg·L^-1,半衰期为2.42 h。展开更多
The unbalance between synaptic(Glu N2 A, mediating the protective pathway) and extrasynaptic NMDA receptors(NMDARs)(Glu N2 B, mediating the excitotoxic pathway) has been found in Alzheimer disease(AD), indicating rest...The unbalance between synaptic(Glu N2 A, mediating the protective pathway) and extrasynaptic NMDA receptors(NMDARs)(Glu N2 B, mediating the excitotoxic pathway) has been found in Alzheimer disease(AD), indicating restoring the balance of Glu N2 A and Glu N2 B should be beneficial for AD therapy. In this study, the Glu N2 B-selective antagonist, ifenprodil, and the non-selective NMDAR agonist, NMDA, had little effects on amyloid-beta(Abeta)-induced long-term potentiation(LTP) deficits.Enhancing the activity of Glu N2 A had a protective effect against Abeta, and specific activation of Glu N2 A and inhibition of Glu N2 B showed a better protective effect. The combination of ifenprodil and D-cycloserine(a co-activator of NMDRs similar to D-serine) led to greater improvement in behavior tests than ifenprodil or D-cycloserine alone, meanwhile, the combination of ifenprodil and D-cycloserine reversed the signal pathway more significantly than ifenprodil or D-cycloserine alone. These results indicate that enhancing synaptic NMDARs and inhibiting extrasynaptic NMDARs concurrently showed protective effects against Abeta-induced neurotoxicity, suggesting that modulation of the balance between Glu N2 A and Glu N2 B might be a good strategy for drug discovery against AD.展开更多
文摘This paper reports the development and validation of an assay for ifenprodil based on liquid chromatography–tandem mass spectrometry(LC–MS/MS)and its application to a pharmacokinetic study involving single and multiple intravenous infusions to healthy Chinese volunteers.After sample preparation of plasma by liquid–liquid extraction with ethyl acetate,the analyte and internal standard,urapidil,were separated by reversed phase chromatography in a run time of 4 min and detected by positive ion electrospray ionization followed by multiple reaction monitoring of the precursor-to-product ion transitions at m/z 326.2-308.1 for ifenprodil and m/z 388.4-205.3 for IS.The assay was linear in the concentration range 0.2–50.0 ng/mL with recovery 476.4%.In the pharmacokinetic study of single intravenous infusions of 5,10 and 15 mg ifenprodil,peak plasma concentrations and areas under the plasma concentration–time curve were both linearly related to dose.In the pharmacokinetic study of multiple once daily intravenous infusions of 10 mg ifenprodil for 7 days,pharmacokinetic parameters were similar to those after the single dose showing that ifenprodil does not accumulate on repeated administration.
文摘The unbalance between synaptic(Glu N2 A, mediating the protective pathway) and extrasynaptic NMDA receptors(NMDARs)(Glu N2 B, mediating the excitotoxic pathway) has been found in Alzheimer disease(AD), indicating restoring the balance of Glu N2 A and Glu N2 B should be beneficial for AD therapy. In this study, the Glu N2 B-selective antagonist, ifenprodil, and the non-selective NMDAR agonist, NMDA, had little effects on amyloid-beta(Abeta)-induced long-term potentiation(LTP) deficits.Enhancing the activity of Glu N2 A had a protective effect against Abeta, and specific activation of Glu N2 A and inhibition of Glu N2 B showed a better protective effect. The combination of ifenprodil and D-cycloserine(a co-activator of NMDRs similar to D-serine) led to greater improvement in behavior tests than ifenprodil or D-cycloserine alone, meanwhile, the combination of ifenprodil and D-cycloserine reversed the signal pathway more significantly than ifenprodil or D-cycloserine alone. These results indicate that enhancing synaptic NMDARs and inhibiting extrasynaptic NMDARs concurrently showed protective effects against Abeta-induced neurotoxicity, suggesting that modulation of the balance between Glu N2 A and Glu N2 B might be a good strategy for drug discovery against AD.
