螺内酯代谢物坎利酮健康人体药动学和相对生物利用度研究.pdf
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1、 硕士学位论文螺内酯代谢物坎利酮健康人体药动学和相对生物利用度研究郑州大学2007届硕士研究生论文螺内能代谢物坎利朋健康人体药动学和相对生物利用度研究螺内酯代谢物坎利酮健康人体药动学和相对生物利用度研究 摘要螺内酯(spironolactone)化学结构与醛固酮相似,是最早使用的醛固酮受 体拮抗药,临床常用于伴有醛固酮升高的顽固性水肿、充血性心力衰竭、高血压 等。随着人们对于醛固酮的生理病理的进一步认识,因而对螺内酯的药理作用的 研究进一步加深,使其临床应用有着更广泛的前景。螺内酯在人体内血药浓度低,代谢速度快,其体内代谢产物为坎利酮(canrenone),坎利酮的药代动力学研 究国内尚无报道
2、。本文以江苏宜兴前进制药厂生产的螺内酯片为标准参比制剂,以江苏长江药业有限公司研制的螺内酯片为被试制剂,通过测定螺内酯的代谢物 坎利酮的浓度对两试剂的相对生物利用度和生物等效性进行研究,为螺内酯的临 床使用提供参考依据。目的 研究坎利酮在健康人体中的药动学及相对生物利用度。方法 采用两周期交叉试验设计,18名受试者随机分为2组,分别口服螺内 酯标准参比制剂和被试制剂,剂量均为200mg,两次试验间隔时间为2周。受试 者试验前体检无肝、肾功能及心脏功能均正常。经志愿受试者本人及家族史调查,本人及家族无过敏体质,受试前两周及试验间未使用过任何其他药物并禁烟酒。受试者于试验前日晚8时后禁食,次日晨用
3、200mL温开水送服受试药物。服药 后4h进相同低脂肪、低蛋白标准餐。分别于给药前,给药后0.5、1、1.5、2、2.5、3、4、6、8、12、24、48、72h 取静脉血 4mL,肝素抗凝,离心 10min(3000r/min)3 取血浆于-20保存待测。采用高效液相色普分析法分析药物浓度:精密吸取血 浆1.0mL,加入乙酸乙酯4mL,旋涡混合5min,离心lOmin(3500 rmin),吸 取上层有机相3mL;于40水浴氮气吹干,用100gL甲醇:水=8:2溶解,40皿郑州大学2007届硕上研究生论文螺内酯代谢物坎利酮健康人体药动学和相对生物利用度研究进样。色普条件为色普柱:色谱柱:Al
4、igentC柱(5|im,4.6mmX200 mm),流动 相:乙礴:0.02M磷酸氢二铁溶液=45:55(v/v);流速;LOmL/min,二极管阵 列检测器,波长:280nm,进样量:40gLo药时数据用3P 97软件经微机处理,根据F检验和AIC值选择房室数,以拟合优度值(goodness of fh)等选择权重。血浆药物峰浓度(:畸)、达峰时间(Tgx)取实测值。结果 本研究用高效液相色普法(HP LC)考察了坎利酮在人体内的药代动力 学过程,方法学考察结果表明该方法专属性强,血浆中杂质不干扰样品测定;坎 利酮的标准曲线回归方程为:C=0.7671A+3.3992(r=0.9999),
5、线性范围为 9.375300Hg七、二者回收率、R内差、日间差均符合生物样品分析要求。研究表明,坎利酮在健康受试者体内过程符合一房室开放模型。两制剂的主 要药动学参数如下:Tmax分别为(4.21.2)h和(4.7L6)h,分别为(159.8士 46.6)gg L1 和(149.743.4)摩1/,分别为(18.184.88)h 和(19.073.88)h,力UC;分另1J为(3168.5688.4)冲山工和(3266.7626.9)AghL”,NUC;分别为(3610.7768.4).心1/和(3758.9641.9)AghL“。与标准参比制剂相比,被试 制剂的相对生物利用度用为(106.3
6、26.0)%,用8为(107.6土25.9)%。对两制剂间 的AU,、Cm等进行方差分析和双向单侧,检验,Tmax采用非参数法 检验,表明两种制剂具有生物等效性。结论1.揭示了坎利酮的健康人体的药动学特点。2.江苏长江药业有限公司研制的螺内酯片与标准参比制剂具有生物等效 性。关键词:螺内酯;坎利酮;HP LC;药动学;生物利用度;生物等效性n郑州大学2007届硕1:研究生论文螺内酯代谢物坎利用健康人体药动学和相对生物利用度研究The Study of Pharmacokinetics and relative Bioavailability of Spironolatone Metabolit
7、e Canrenone in Healthy Chinese Volunteers AbstractSpironolactone,the first used aldosterone receptor antagonist,has a very similar chemical structure with aldosterone,and its now being wildly used on patients with edema with aldosterone elevation,congestive heart failure,and hypertension etc.As peop
8、le are acquiring more and more knowledge in the physiopathology of aldosterone,the research of the pharmacological action of spironolactone will be pushed further,making it a broader future in clinical use.Having a short metabolism rate,spironolactone has a low plasma concentration rate in human bod
9、y.Its metabolite is canrenone,which has no pharmacokinetics study reported in our country yet.The pharmacokinetics about canrenone,metabolites of spironolactone(both Jiangsu Yixing Qiaiyin medical co.and Jiangsu Changjiang medical co.),in Chinese healthy volunteers is reported in this thesis and it
10、will provide academic foundation for the development and clinical use of spironolactone.Objective To study pharmacokinetics academic foundation and clinical use of canrenone.Methods A single oral dose 200mg of two spironolactone oral solutions was given two 18 healthy volunteers in a randomized cros
11、s-over study.The interval was 2 weeks.None of the subjects had a history of significant medical illness or hypersensitivity to any drugs.They were not alcohol addicted and were none-smoker.None of them had taken any other drugs during the study.Their in郑州人学2007届硕I:研究生论文螺内的代谢物坎利酮健康人体药助学和相对生物利用度研究norm
12、al health status were judged on the basis of a physical examination with screening blood chemistries,including a complete blood count and liver function test,urinalysis and eletrocardiogram performed before the study.After overnight fast,each of them took a single 200mg oral dose of spironolactone w
13、ith 200ml water.A standardized meal was served separately at 4 hours after the drug ingestion.Venous blood samples(4ml each)were collected into heparin zed tubes,inunediately before the drug administration and at 0.5,1,L5,2,2.5,3,4,6,8,12,24,48,72 hours after dosing.The sample were spun immediately
14、after the collection,centrifuged for 10 min at 3000 r/min,and the plasma samples were stored at-200C until assayed.Then 1.0 ml plasma was taken to a clean tube,4ml ethyl acetate was added to each tube for extraction,tube were vortexed vigorously for 5 min,centrifiiged for 10 min at 3000 r/min,and th
15、e 3tnl organic layer was evaporated at 40 0 C under conditions of a mild nitrogen.When the tube was dry,acetonitrile:0.02M ammonium dibasic phosphater(45:55),P H 5.6,was added for reconstitution.Tubes were vortexed vigorously for 1 min9and 40HL was injected via Agilient Crop.The sample was delivered
16、 using a mobile phase composed of 45%acetonitrile and 55%0.05M monobasic ammonium phosphate at 280 nm.The plasma concentration-time data were disposed with 3P 97 program.The peak connection(Cmax)and the peak time(Tmax)of nevirapine were determined from the respective observed concentration-time data
17、.The area under the curve(AUC)was calculated by the linear trapezoidal method.The data are expressed as mean values SD throughout the paper.Difference in pharmacokinetics data of two formulation were evaluated statistically by use of a two-one side t test.P value of 0.05 was considered to statistica
18、lly significant.Results The results showed that this method was specific and selective for canrenone in plasma and impurity substance in plasma didn t intefere with determination of canrenone.Obtained linear regression equation of metformin was:C=0.7671A+3.3992(r 0.9999).The method was validated for
19、 a linear range of 9.375-SOOgg-L1 for canrenone.Difference intra-day,intra-day and relative recoveries,all meet with the examination of living creature sample.The study result showed that the data of the two formulations were fitted to郑州大学2007届硕士研究生论文 螺内醋代谢物坎利用日康人体茸动学和相对生物利用度研究a one-compartment open
20、 model in healthy volunteers.Compared with standard reference formulation,the relative bioavailability of canrenone-The main pharmacokinetics parameters two canrenone were as follows:Tmax were(4.2 1,2)h and(4.71.6)h,Cmax were(159.8 46.6)gg-Ld and(149.7 43.gg-L1,Ti/2kCwere(I8J84.88)h and(19.073.88)h,
21、AUC were(3168.5688.4)|ig h Land(3266.7626.9)AghL“,AUC;were(3610.7768,4)ug h-Lq and(3758.9 641.9)p.g h-L1,respectively.The relative bioavailability of Fq was(1063 26.0)%,and 琦 was(107.625.9)%.The results of ANOVA and two one-side t test statically analysis showed that the two spironolactone were bioe
22、quivalent.Conclusions1.The process show the pharmacokineHcs academic foundation of canrenone in healthy volunteers.2 The spironolactone(both Jiangsu Yixing Qianjin medical co.and Jiangsu Changjiang medical co.)have the similar pharmacokinetics parameters,and they are bioequivalent.Key words spironol
23、actone;canrenone;HP LC;pharmacokinetics;bioequivalencev郑州大学2007届硕1.研究生论文螺内前代谢物坎利酮健康人体药动学和相对生物利用度研究螺内酯代谢物坎利酮健康人体药动学和 相对生物利用度研究 前言螺内酯(spironolactone)又名安体舒通(antisterone),化学名为(7 a,17a)-7-(乙酰基硫基)-17-羟基-3-氧代孕街-4-烯-21-竣酸Y-内酯,是由美 国辉瑞公司研发的盐皮质类固醇拮抗剂。螺内酯匕及短,进入体内后迅速被代谢,活性代谢产物为坎利酮(canrenone)和7硫甲基螺内酯(7 a-thionmet
24、hylspirolactone)。螺内酯化学结构与 醛固酮相似,是临床最早使用的醛固酮受体拮抗药。可竞争性的与胞浆中的醛固 酮受体结合,拮抗醛固酮的排钾保钠作用,促进NI和水的排出,减少K+的分泌巴 由于此药仅作用于远曲小管和集合管,对肾小管其他段无作用,故利尿作用较弱,其利尿作用与体内醛固酮水平有关。属于保钾利尿药。临床在高血压的治疗中常 与唾嗪类利尿药联合应用预防低血钾叫在心力衰竭治疗中应用ACE抑制药的基础上加用螺内酯的作用机制除了最初 的利尿作用外,还具有降低心肌胶原蛋白合成,抑制心肌纤维化,纠正低血镁,改善神经内分泌的作用。螺内酯应用可干预醛固酮逃逸现象,阻断醛固酮的作用,可显著降低
25、由于心力衰竭的总病死率和住院时间。近期的螺内酯随机评价研究 证实螺内酯能显著降低心衰和急性心肌梗死(AMI)后心衰患者的病死率。心肌纤维化是致心律失常的重要原因之一,所以螺内酯可以通过抗纤维化作 用而抗心律失常。有研究证实螺内酯可改善心肌交感神经活性。而且螺内酯具 有拟副交感神经作用,从而对心衰患者室性心律失常起到附加抑制作用。在高 血压治疗中,螺内酯常与其他利尿剂联合使用避免出现低血钾、低血镁。一系列报道证实,螺内酯具有预防减轻组织器官纤维化的作用。Lacolley 等证实螺内酯可预防大鼠心肌及动脉周围纤维形成,Tsutamoto等对20例慢性 充血性心衰病人用螺内酯4个月后,血浆P III
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