厄贝沙坦和氨氯地平的协同降压作用及其药代动力学研究
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摘要
高血压病是一种具有多种不同发病机制的疾病，它不仅是血流动力学异常疾病，而且也伴随脂肪、糖代谢紊乱和心、脑、肾等靶器官的不良重塑，其心、脑、肾并发症、病死率、致残率都很高。血压波动性(blood pressure variability, BPV)异常在高血压病人中非常普遍，并且是独立于血压升高之外造成器官损伤并增加并发症的一个危险因素。因此，高血压的治疗要在有效控制血压水平的同时，还要考虑对BPV的控制，并且预防和逆转靶器官的不良重构，这是降低心血管并发症的发生和病死率的关键。单一药物治疗简便、花费少，但它有一定局限性，有许多缺点如血压控制率低(仅45-50％的病人血压在单一药物治疗时得到控制)、不良反应多、有并发症的情况下限制了某些药物的应用等。联合用药近年来受到广泛关注，并作为JNC-VI及WHO／ISH降压指南药物治疗重要原则之一。联合用药可增大降压效果、增加控制率、减少药物的副作用、增进病人的依从性和降低治疗成本等。临床上只有50％的病人血压在单一药物治疗时得到了较好的控制。相反，两药或多种药物联合应用时，80—90％的病人血压可以得到控制。根据以上抗高血压药物的治疗原则和研究趋势，本课题选择广泛用于抗高血压治疗的两种药物长效二氢吡啶类钙通道阻滞药氨氯地平和新型选择性血管紧张素AT_1受体拮抗剂厄贝沙坦为主要研究对象，第一部分研究其单药及联合应用对血压波动性是否有降低作用，二者联合应用在降压、降低BPV及器官保护方面是否有协同作用。第二部分对两药联合应用的药代动力学进行了研究。
本课题主要研究内容包括：
1．厄贝沙坦、氨氯地平联合用药的协同作用
观察厄贝沙坦(irbesartan，Irb)和氨氯地平(amlodipine，Aml)对降低自发性高血压大鼠(spontaneously hypertensive rat，SHR)的血压及血压波动性以及靶器官保护的协同作用。
急性治疗实验中，实验分为八组：0.8％的羧甲基纤维素钠组(空白对照组)，氨氯地平单用三个剂量组(0.5，1.0，2.0 mg／kg)，厄贝沙坦组(50mg／kg)，厄贝沙坦+氨氯地平三个剂量组(50+0.5，50+1.0，50+2.0 mg／kg)，每组8只动物。连续记录给药后25小时内的血压和心动间期，观察收缩压，舒张压及其波动性和心动间期的变化情况。以q值法评价急性给药后两药对SHR降压，稳定血压的协同作用。实验结果表明厄贝沙坦和氨氯地平以50：1的剂量联用时，在降低血压和降低血压波动性方面具有明显协同作用。
长期治疗实验共分六组：空白对照组，氨氯地平组(1.0 mg／kg／d)，厄贝沙坦组(50mg／kg／d)，厄贝沙坦+氨氯地平三个剂量组(25+0.5，50+1.0，50+2.0 mg／kg／d)，每组动物8只，治疗四个月后，连续记录5小时收缩压和舒张压，然后将动物断头处死，取心脏和主动脉进行形态学测定。以q值法评价急性给药后两药对SHR降压，稳定血压及减轻器官损伤的协同作用。实验结果表明厄贝沙坦和氨氯地平以50+1 mg／kg／d的剂量联用时，对自发性高血压大鼠的血压控制及器官保护协同作用效果最佳。
2．氨氯地平和厄贝沙坦合并用药的药代动力学相互影响
本实验选择6条成年、健康比格犬随机分成三组，采用自身对照、随机交叉试验方法，研究江苏恒瑞医药股份有限公司研制的厄贝沙坦氨氯地平片(规格：每片含氨氯地平1mg，厄贝沙坦50mg)在比格犬体内的单剂量药代动力学与合并用药相互作用，其中厄贝沙坦氨氯地平片复方实验药物选择含氨氯地平5mg，厄贝沙坦250mg的氨氯地平和厄贝沙坦混合粉末，对照药物分别为含氨氯地平5mg的氨氯地平粉末和250mg厄贝沙坦药物粉末，通过临床前药代动力学研究，分别估算以氨氯地平和厄贝沙坦表征的厄贝沙坦氨氯地平片复方实验药物的相对生物利用度和其它药代动力学参数。
建立的血浆样品中氨氯地平的LC／MS／MS测定方法，血浆内源性物质及其它物质均不干扰氨氯地平样品峰，相对回收率大于90.0％，日间和日内相对标准差小于15.0％，血浆中氨氯地平的最低定量限为4.99ng／ml，线性范围为4.99～499ng／ml。说明该方法符合生物样品的分析要求，可以用于以氨氯地平表征的厄贝沙坦氨氯地平复方试验药物的临床前药代动力学研究。
建立的血浆样品中厄贝沙坦的反相高效液相色谱测定方法，血浆内源性物质及其它物质均不干扰厄贝沙坦样品峰，相对回收率大于90.0％，日间和日内相对标准差小于10.0％，血浆中厄贝沙坦的最低定量限为10.01ng／ml，线性范围为10.01～5005.00ng／ml。说明该方法符合生物样品的分析要求，可以用于以厄贝沙坦表征的厄贝沙坦氨氯地平复方试验药物的临床前药代动力学研究。
单剂量实验结果表明：以氨氯地平表征的厄贝沙坦氨氯地平复方实验药物(以氨氯地平计5mg，厄贝沙坦250mg)的相对生物利用度为104％±14.4％(84.2％～119％)，生物利用度符合要求。进一步对lnC_(max)、lnAUC_(0～72)进行双单侧t检验，结果显示厄贝沙坦氨氯地平复方实验药物(以氨氯地平计5mg，厄贝沙坦250mg)和氨氯地平对照药物(给药剂量以氨氯地平计5mg)双单侧t检验合格，即单用氨氯地平及与厄贝沙坦合用(厄贝沙坦氨氯地平复方试验药物)时氨氯地平的主要药代动力学参数无明显改变，表明厄贝沙坦氨氯地平复方实验药物合并用药不存在药代动力学相互影响。
以厄贝沙坦表征的厄贝沙坦氨氯地平复方实验药物(以氨氯地平计5mg，厄贝沙坦250mg)的相对生物利用度为99.7％±10.5％(83.4％～110％)，生物利用度符合要求。进一步对lnC_(max)、lnAUC_(0～48)进行双单侧t检验，结果显示厄贝沙坦氨氯地平复方试验药物(以氨氯地平计5mg，厄贝沙坦250mg)和厄贝沙坦对照药物(给药剂量为250mg)双单侧t检验合格，即单用厄贝沙坦及与氨氯地平合用(厄贝沙坦氨氯地平复方试验药物)时厄贝沙坦的主要药代动力学参数无明显改变，表明厄贝沙坦氨氯地平复方实验药物合并用药不存在明显的药代动力学相互影响。
Hypertension is one of the most common cardiovascular diseases. It alwaysleads to complications of heart, kidney and brain etc. We know that the higher thelevel of blood pressure is, the severer the target organ damages are. Thus, the keypoint of anti-hypertension is to low effectively blood pressure and prevent well organdamages But things are not so simple Howerve high BP level is not the unique factordetermining hypertensive organ damage. Evidences have shown that blood pressurevariability (BPV) is also an important factor determining end organ damage inhypertension. Therefore, decreasing BPV should be considered when blood pressurelevel is controlled. Researches on anti-hypertensive drugs made much progress inrecent years, but the total rate control is still far from optimality. Combination of twoor three antihypertensive drugs gained more and more attention these years for itsadvantages in simplifying dosing regimens, improving patients' compliance,increasing rate control to 70％, decreasing dose-dependent side effects and reducingcost compared to monotherapy. According to the therapeutic principles and trends ofstudies, we mainly studied the synergic effect of combination therapy and thepharmacokinetics of combination. The ingredients in our combination therapy areirbesartan (angiotension receptor 1 antagonist, Irb) and amlodipine (calcium channelblocker, Aml).
There are two parts in the present study:
1. Possible synergism of Irbesartan and Amlodipine
This part was designed to investigate the possible synergism of Irbesartan andAmlodipine on lowering blooding pressure and BPV, and on organ protection inspontaneously hypertensive rats (SHR).
In the acute therapy, sixty-four SHR were randomly divided into 8 groups. Theywere respectively given 0.8％carboxymethylcellulose sodium (control), Irbesartan (50 mg/kg), Amlodipine (0.5, 1, 2 mg/kg) and the combinations of Irbesartan andAmlodipine (50+0.5, 50+1, and 50+2 mg/kg). The drugs were given via a catheterof gastric fistula. Blood pressure was recorded from one hour before drugadministration for 25 hours in conscious freely moving condition of SHR. q value testwas performed to assess the synergism of two antihypertensive drugs on BP and BPVreduction. It was found that combination of Irbsartan and Amlodipine significantlydecreased blood pressure (SBP) and systolic blood pressure variability (SBPV).According to probability sum analysis, it was found that proportion of Irbsartan andAmlodipine=50:1 was the best combination (q=1.23).
In long-term therapy, 6 groups were set: Amlodipine (1.0 mg/kg/d), Irbesartan(50mg/kg/d), and the combinations of Irbesartan and Amlodipine (25+0.5, 50+1.0,50+2.0 mg/kg/d). Drugs were mixed into rat chow. The ingredient and content ofdrugs in chow was calculated according to theoretically estimated drug doses andfood consumption previously recorded. The control groups received normal rat chowwithout any drugs. 16 weeks later, BP and BPV were recorded for 5 hours, then therats was weighed and killed by decapitation. The aorta and heart was excised andrinsed in cold physiological saline. Organ damage was estimated by observation ofmorphologic changes. The q value test was performed to assess the synergism of twoantihypertensive drugs on BP and BPV reduction and organ protection. It was foundthat the combination of Irbsartan and Amlodipine at 50+1 mg/kg/d synergized themost optimally.
In conclusion, this part clearly demonstrated that the combination of Irbesartanand Amlodipine is synergistic in lowering and stabilizing BP and organ protection.The synergism is greatest when the dose proportion of the two drugs is 50:1.
2. Pharmacokinetics of compound preparation of Irbesartan and Amlodipine
Six adult healthy beagle dogs in a randomized 2-way crossover study, dividedinto three groups, were given a single oral dose of compound powder of amlodipineand irbesartan (containing 5 mg amlodipine and 250 mg irbesartan), 5 mg amlodipinepowder and 250 mg irbesartan powder respectively. The pharmacokinetics and bioequivalence of amlodipine powder and compound amlodipine and irbesartan(represented by amlodipine), irbesartan powder and compound amlodipine andirbesartan (represented by irbesartan) were compared. The plasma concentrations ofamlodipine and irbesartan were measured by high performance liquidchromatography-electrospray ionization tandem mass spectrometry. No matrix effectwas observed to interfere the peak of amlodipine and irbesartan. The relative recoveryof amlodipine and irbesartan were both above 90％. The relative standard deviation ofinter-day and intra-day of arnlodipine and irbesartan were below 10％and 15％,respectively. The lower limit of quantitation of amlodipine and irbesartan in plasmawere 4.99 ng/ml and 10.01ng/ml, with the linear range 4.99-499.00 ng/ml and10.01-5005.00 ng/ml, respectively. No significant difference appears in thepharmacokinetic parameters between the formulations. The relative bioavailability ofcompound amlodipine and irbesartan (represented by amlodipine) is104.06％±14.36％. The AUC and Cmax between the two formulations, amlodipinepowder and compound amlodipine and irbesartan (represented by amlodipine) arebioequivalent. The relative bioavailability of compound amlodipine and irbesartan(represented by irbesartan) is 99.7％±10.5％. The AUC and Cmax between the twoformulations, irbesartan powder and compound amlodipine and irbesartan(represented by irbesartan) are bioequivalent. The sesults show that the combinationof amlodipine and irbesartan has not influence each other in pharmacokinetics.
本课题主要研究内容包括：
1．厄贝沙坦、氨氯地平联合用药的协同作用
观察厄贝沙坦(irbesartan，Irb)和氨氯地平(amlodipine，Aml)对降低自发性高血压大鼠(spontaneously hypertensive rat，SHR)的血压及血压波动性以及靶器官保护的协同作用。
急性治疗实验中，实验分为八组：0.8％的羧甲基纤维素钠组(空白对照组)，氨氯地平单用三个剂量组(0.5，1.0，2.0 mg／kg)，厄贝沙坦组(50mg／kg)，厄贝沙坦+氨氯地平三个剂量组(50+0.5，50+1.0，50+2.0 mg／kg)，每组8只动物。连续记录给药后25小时内的血压和心动间期，观察收缩压，舒张压及其波动性和心动间期的变化情况。以q值法评价急性给药后两药对SHR降压，稳定血压的协同作用。实验结果表明厄贝沙坦和氨氯地平以50：1的剂量联用时，在降低血压和降低血压波动性方面具有明显协同作用。
长期治疗实验共分六组：空白对照组，氨氯地平组(1.0 mg／kg／d)，厄贝沙坦组(50mg／kg／d)，厄贝沙坦+氨氯地平三个剂量组(25+0.5，50+1.0，50+2.0 mg／kg／d)，每组动物8只，治疗四个月后，连续记录5小时收缩压和舒张压，然后将动物断头处死，取心脏和主动脉进行形态学测定。以q值法评价急性给药后两药对SHR降压，稳定血压及减轻器官损伤的协同作用。实验结果表明厄贝沙坦和氨氯地平以50+1 mg／kg／d的剂量联用时，对自发性高血压大鼠的血压控制及器官保护协同作用效果最佳。
2．氨氯地平和厄贝沙坦合并用药的药代动力学相互影响
本实验选择6条成年、健康比格犬随机分成三组，采用自身对照、随机交叉试验方法，研究江苏恒瑞医药股份有限公司研制的厄贝沙坦氨氯地平片(规格：每片含氨氯地平1mg，厄贝沙坦50mg)在比格犬体内的单剂量药代动力学与合并用药相互作用，其中厄贝沙坦氨氯地平片复方实验药物选择含氨氯地平5mg，厄贝沙坦250mg的氨氯地平和厄贝沙坦混合粉末，对照药物分别为含氨氯地平5mg的氨氯地平粉末和250mg厄贝沙坦药物粉末，通过临床前药代动力学研究，分别估算以氨氯地平和厄贝沙坦表征的厄贝沙坦氨氯地平片复方实验药物的相对生物利用度和其它药代动力学参数。
建立的血浆样品中氨氯地平的LC／MS／MS测定方法，血浆内源性物质及其它物质均不干扰氨氯地平样品峰，相对回收率大于90.0％，日间和日内相对标准差小于15.0％，血浆中氨氯地平的最低定量限为4.99ng／ml，线性范围为4.99～499ng／ml。说明该方法符合生物样品的分析要求，可以用于以氨氯地平表征的厄贝沙坦氨氯地平复方试验药物的临床前药代动力学研究。
建立的血浆样品中厄贝沙坦的反相高效液相色谱测定方法，血浆内源性物质及其它物质均不干扰厄贝沙坦样品峰，相对回收率大于90.0％，日间和日内相对标准差小于10.0％，血浆中厄贝沙坦的最低定量限为10.01ng／ml，线性范围为10.01～5005.00ng／ml。说明该方法符合生物样品的分析要求，可以用于以厄贝沙坦表征的厄贝沙坦氨氯地平复方试验药物的临床前药代动力学研究。
单剂量实验结果表明：以氨氯地平表征的厄贝沙坦氨氯地平复方实验药物(以氨氯地平计5mg，厄贝沙坦250mg)的相对生物利用度为104％±14.4％(84.2％～119％)，生物利用度符合要求。进一步对lnC_(max)、lnAUC_(0～72)进行双单侧t检验，结果显示厄贝沙坦氨氯地平复方实验药物(以氨氯地平计5mg，厄贝沙坦250mg)和氨氯地平对照药物(给药剂量以氨氯地平计5mg)双单侧t检验合格，即单用氨氯地平及与厄贝沙坦合用(厄贝沙坦氨氯地平复方试验药物)时氨氯地平的主要药代动力学参数无明显改变，表明厄贝沙坦氨氯地平复方实验药物合并用药不存在药代动力学相互影响。
以厄贝沙坦表征的厄贝沙坦氨氯地平复方实验药物(以氨氯地平计5mg，厄贝沙坦250mg)的相对生物利用度为99.7％±10.5％(83.4％～110％)，生物利用度符合要求。进一步对lnC_(max)、lnAUC_(0～48)进行双单侧t检验，结果显示厄贝沙坦氨氯地平复方试验药物(以氨氯地平计5mg，厄贝沙坦250mg)和厄贝沙坦对照药物(给药剂量为250mg)双单侧t检验合格，即单用厄贝沙坦及与氨氯地平合用(厄贝沙坦氨氯地平复方试验药物)时厄贝沙坦的主要药代动力学参数无明显改变，表明厄贝沙坦氨氯地平复方实验药物合并用药不存在明显的药代动力学相互影响。
Hypertension is one of the most common cardiovascular diseases. It alwaysleads to complications of heart, kidney and brain etc. We know that the higher thelevel of blood pressure is, the severer the target organ damages are. Thus, the keypoint of anti-hypertension is to low effectively blood pressure and prevent well organdamages But things are not so simple Howerve high BP level is not the unique factordetermining hypertensive organ damage. Evidences have shown that blood pressurevariability (BPV) is also an important factor determining end organ damage inhypertension. Therefore, decreasing BPV should be considered when blood pressurelevel is controlled. Researches on anti-hypertensive drugs made much progress inrecent years, but the total rate control is still far from optimality. Combination of twoor three antihypertensive drugs gained more and more attention these years for itsadvantages in simplifying dosing regimens, improving patients' compliance,increasing rate control to 70％, decreasing dose-dependent side effects and reducingcost compared to monotherapy. According to the therapeutic principles and trends ofstudies, we mainly studied the synergic effect of combination therapy and thepharmacokinetics of combination. The ingredients in our combination therapy areirbesartan (angiotension receptor 1 antagonist, Irb) and amlodipine (calcium channelblocker, Aml).
There are two parts in the present study:
1. Possible synergism of Irbesartan and Amlodipine
This part was designed to investigate the possible synergism of Irbesartan andAmlodipine on lowering blooding pressure and BPV, and on organ protection inspontaneously hypertensive rats (SHR).
In the acute therapy, sixty-four SHR were randomly divided into 8 groups. Theywere respectively given 0.8％carboxymethylcellulose sodium (control), Irbesartan (50 mg/kg), Amlodipine (0.5, 1, 2 mg/kg) and the combinations of Irbesartan andAmlodipine (50+0.5, 50+1, and 50+2 mg/kg). The drugs were given via a catheterof gastric fistula. Blood pressure was recorded from one hour before drugadministration for 25 hours in conscious freely moving condition of SHR. q value testwas performed to assess the synergism of two antihypertensive drugs on BP and BPVreduction. It was found that combination of Irbsartan and Amlodipine significantlydecreased blood pressure (SBP) and systolic blood pressure variability (SBPV).According to probability sum analysis, it was found that proportion of Irbsartan andAmlodipine=50:1 was the best combination (q=1.23).
In long-term therapy, 6 groups were set: Amlodipine (1.0 mg/kg/d), Irbesartan(50mg/kg/d), and the combinations of Irbesartan and Amlodipine (25+0.5, 50+1.0,50+2.0 mg/kg/d). Drugs were mixed into rat chow. The ingredient and content ofdrugs in chow was calculated according to theoretically estimated drug doses andfood consumption previously recorded. The control groups received normal rat chowwithout any drugs. 16 weeks later, BP and BPV were recorded for 5 hours, then therats was weighed and killed by decapitation. The aorta and heart was excised andrinsed in cold physiological saline. Organ damage was estimated by observation ofmorphologic changes. The q value test was performed to assess the synergism of twoantihypertensive drugs on BP and BPV reduction and organ protection. It was foundthat the combination of Irbsartan and Amlodipine at 50+1 mg/kg/d synergized themost optimally.
In conclusion, this part clearly demonstrated that the combination of Irbesartanand Amlodipine is synergistic in lowering and stabilizing BP and organ protection.The synergism is greatest when the dose proportion of the two drugs is 50:1.
2. Pharmacokinetics of compound preparation of Irbesartan and Amlodipine
Six adult healthy beagle dogs in a randomized 2-way crossover study, dividedinto three groups, were given a single oral dose of compound powder of amlodipineand irbesartan (containing 5 mg amlodipine and 250 mg irbesartan), 5 mg amlodipinepowder and 250 mg irbesartan powder respectively. The pharmacokinetics and bioequivalence of amlodipine powder and compound amlodipine and irbesartan(represented by amlodipine), irbesartan powder and compound amlodipine andirbesartan (represented by irbesartan) were compared. The plasma concentrations ofamlodipine and irbesartan were measured by high performance liquidchromatography-electrospray ionization tandem mass spectrometry. No matrix effectwas observed to interfere the peak of amlodipine and irbesartan. The relative recoveryof amlodipine and irbesartan were both above 90％. The relative standard deviation ofinter-day and intra-day of arnlodipine and irbesartan were below 10％and 15％,respectively. The lower limit of quantitation of amlodipine and irbesartan in plasmawere 4.99 ng/ml and 10.01ng/ml, with the linear range 4.99-499.00 ng/ml and10.01-5005.00 ng/ml, respectively. No significant difference appears in thepharmacokinetic parameters between the formulations. The relative bioavailability ofcompound amlodipine and irbesartan (represented by amlodipine) is104.06％±14.36％. The AUC and Cmax between the two formulations, amlodipinepowder and compound amlodipine and irbesartan (represented by amlodipine) arebioequivalent. The relative bioavailability of compound amlodipine and irbesartan(represented by irbesartan) is 99.7％±10.5％. The AUC and Cmax between the twoformulations, irbesartan powder and compound amlodipine and irbesartan(represented by irbesartan) are bioequivalent. The sesults show that the combinationof amlodipine and irbesartan has not influence each other in pharmacokinetics.
引文
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3. Shan ZZ, Dai SM, Su DF. Relationship between baroreceptor reflex function and end-organ damage in spontaneously hypertensive rats. Am J Physiol 1999; 277: H1200-6.
4. Su DF and Miao CY. Reduction of blood pressure variability: a new strategy for the treatment of hypertension. Trends Pharmacol Sci 2005; 26: 388-90.
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6. WHO-ISH Hypertension Guideline Committee. 1999 WHO/ISH Guideline for the management of hypertension. J Hypertension 1999; 17:151-85.
7. Stason WB, Schmid CH, Niedzwiecki D, et al. Safety of nifedipine in patients with hypertension: a meta-analysis. Hypertension. 1997; 30(1 Pt 1):7-14.
8. Xie HH, Chen YY, Miao CY, et al.. Effects of long-term treatment with candesartan on hemodynamics and organ damage in spontaneously hypertensive rats.
9．程勇，张洪，苏定冯．计算机化清醒自由活动法血流动力学测定技术．中国药理学通报 1990；6：392-4．
10. Jin ZJ. About the evaluation of drug combination. Acta Pharmacol Sin 2004; 25(2):146-7.
11. Xie HH, Miao CY, Jiang YY, Su DF. Synergism of atenolol and nitrendipine on hemodynamic amelioration and organ protection in hypertensive rats. J Hypertens 2005; 23:193-201.
12. Burges R, Moisey D. Unique pharmacologic properties of amlodipine. Am J Cardiol 1994; 73(3):2A-9A.
13. Nakamura Y, Ono H, Frohlich ED. Differential effect of T- and L-type calcium antagonists on glomerular dynamics in spontaneously hypertensive rats. Hypertension 1999; 34:273-8.
14. Zhou X, Ono H, Ono Y, Frohlich ED. N- and L-type calcium channel antagonist improves glomerular dynamics, reverses severe nephrosclerosis, and inhibits apoptosis and prolifteration in an L-NAME/SHR model. J Hypertens 2002; 20(5): 993-1000.
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16．胡钢英．血管紧张素Ⅱ受体阻滞剂的临床研究现状．国外医学·内科学分册．2001；28(4)：143-6．
17. Waeber B. A review of irbesartan in antihypertensive therapy: comparison with other antihypertensive agents. Curr Ther Res Clin Exp 2001; 62:505-23.
18. Malmqvist K, Kahan T, Edner M, and Bergfeldt L. Comparison of actions of irbesartan versus atenolol on cardiac repolarization in hypertensive left ventricular hypertrophy: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation Versus Atenolol (SILVHIA). Am J Cardiol 2002; 90(10): 1107-12.
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