【作者】 张志清；

【导师】 王永利；

【作者基本信息】 河北医科大学 ， 药理学， 2006， 博士

【摘要】 间尼索地平化学名称:1,4-二氢-2,6-二甲基-4-(3-硝基苯基)-3,5-吡啶二羧酸甲酯异丁酯,为尼索地平的同分异构体,系河北医科大学药学院合成的新分子实体药物。通过结构改造,间尼索地平对光稳定性明显改善。大量药效学研究已经表明,间尼索地平具有与尼索地平相似的药理作用,且其对血管选择性高,对动脉收缩的抑制作用强,降压作用持续时间长,而对心肌的负性变力作用弱,在多方面优于尼索地平,展现出其有望成为一个更理想的抗高血压一类新药的光辉前景。但目前对其药代动力学研究资料尚少,仅在大鼠和家兔进行了一般药动学研究。本文拟建立恒河猴及Beagle犬血浆中间尼索地平的HPLC测定方法,旨在进一步研究恒河猴及Beagle犬静脉注射间尼索地平后体内药代动力学行为,并对Beagle犬口服大剂量间尼索地平后体内的毒代动力学特征进行探讨。第一部分恒河猴静脉注射间尼索地平体内药代动力学研究目的:建立恒河猴血浆中间尼索地平的HPLC测定方法,研究静脉注射给药后间尼索地平在恒河猴体内的药代动力学特征。方法:(1)给药方法及血浆样品采集:恒河猴15只,随机分为低、中、高三个剂量组,分别静脉注射0.2 mg/kg,0.4 mg/kg和0.6 mg/kg间尼索地平注射液,给药后不同时间取血浆样品,-40℃低温保存。(2)血浆样品处理:吸取血浆1.0 ml,加入含内标的甲醇溶液及1 mol/L的NaOH溶液混匀,提取液(乙醚:正己烷=1:1 v/v)提取,离心,氮气吹干后以60μl甲醇溶解进样。(3)色谱条件:WatersμBondapak C18色谱柱(3.9×300 mm,10μm),柱温30℃,流动相甲醇-水(63:37),流速1.0 ml/min,检测波长236 nm,进样量20μl,尼莫地平为内标。(4)最低检测限的确定:用倍比稀释法确定最低检测限。(5)标准曲线的制备:配制1.75,3.5,7,14,28,56,112,224,448μg/L的间尼索地平血浆样品,按血浆样品处更多还原

【Abstract】 M-nisoldipine [3-isobutyl-5-methyl 1, 4 -dehydro-2,6 -dimethyl-4-(3- nitrophenyl ) -pyridine-3, 5-dicarboxylate, m-Nis ], an isomer of nisoldipine, is a new drug synthesized by Pharmacy College of Hebei Medical University, School of Pharmacy. By doing structure modification, the light stability of m-nisoldipine improved significantly compared to nisoldipine. Pharmacodynamics studies indicate that the pharmacological actions of m-nisoldipine are similar to nisoldipine. M-nisoldipine has a high selectivity to blood vessels, a powerful inhibitive effect to arterial contraction, a long term hypotension effect and a weak negative inotropic action to cardiac muscles, suggesting that m-nisoldipine is more efficient than nisoldipine and it has a prospect to become an ideal anti-hypertension medicine. Currently, the only pharmacokinetic study of m-nisoldipine was on rats and rabbits. The information about pharmacokinetic study of m-nisoldipine was limited.In this study, we established HPLC methods to determine the plasma m-nisoldipine concentration in Beagle dogs and Rhesus monkeys, study the pharmacokinetics of m-nisoldipine in Beagle dogs and Rhesus monkeys after intravenous administration, and investigate the toxicokinetics of m-nisoldipine in Beagle dogs after oral administration at high doses.PART ONE Study on the pharmacokinetics of m-nisoldipine in Rhesus monkeys after intravenous administrationOBJECTIVE: To establish a HPLC method for the determination of plasma concentration of m-nisoldipine in Rhesus monkeys, and to study the pharmacokinetics of m-nisoldipine after intravenous administration in Rhesus monkeys.METHODS: (1) Medication and plasma samples collection: Fifteen更多还原