【作者】 肖峰；

【导师】 魏伟；

【作者基本信息】 安徽医科大学 ， 药理学， 2008， 硕士

【摘要】 目的:艾拉莫德（Iguratimod）化学名为:3-甲酰胺基-7-甲磺酰胺基-6-苯氧基-4H-1-苯丙吡喃-4-酮,为一种甲磺酰胺类非甾体抗炎药（non-storoidal antiinflammatorydrugs,NSAIDs）,它不仅能选择性抑制环氧酶-2（cycloxygenase-2,COX-2）,而且具有免疫调节作用,比已有的同类药物有更好的疗效和更少的不良反应。治疗类风湿关节炎（rheumatoid arthritis,RA）的临床药理学特征为起效迅速、可减轻炎症肿胀、缓解疼痛和改善功能。文献报道艾拉莫德是通过选择性抑制COX-2而减少炎症组织中前列腺素（prostaglandin,PG）的产生,起到抗炎镇痛作用。尽管目前对艾拉莫德的药理作用研究较多,但是艾拉莫德的在动物或人体中的药动学特点目前还不清楚。本课题在建立大鼠佐剂性关节炎（adjuvant arthritis,AA）模型的基础上,灌胃给予艾拉莫德,同时募集健康志愿者,单次、多次口服给予艾拉莫德以及饮食后给予艾拉莫德,计算T_max、C_max、t_1/2、曲线下面积（areaunder curve,AUC）等药动学参数,为艾拉莫德在临床上合理应用提供实验依据。方法:建立大鼠和健康志愿者血清中艾拉莫德的高效液相色谱（high performanceliquid chromatography,HPLC）测定方法。大鼠灌胃给予艾拉莫德,分为正常组(6mg·kg^-1)和关节炎模型组(3、6、12mg·kg^-1三个剂量组);在健康志愿受试者中,分单次给药（25、50和75mg）、连续给药（25mg）以及进食后给药（50mg）。采用HPLC法测定大鼠和健康志愿受试者血清中艾拉莫德的浓度。利用DAS软件计算T_max、C_max、t_1/2、曲线下面积（area under curve,AUC）等药动学参数。结果1.大鼠和健康志愿受试者血清中艾拉莫德峰和内标峰与杂质峰可完全分离,具有较高的专属性,血清中的杂质不干扰样品的测定,可测定血清中艾拉莫德最低浓度为0.10 mg·L^-1,线性范围分别为0.28-18 mg·L^-1和0.10～10 mg·L^-1,相对回收率＞90%,日内和日间RSD＜5%。2.连续给药后,正常组大鼠(6 mg·kg^-1)的主要药动学参数为:t_1/2Ke:6.30h;t_peak:4.00h;C_max:8.87 mg·L^-1;AUC_0-24:98.52 mg·L^-1·h。AA大鼠低、中、高三个剂量组(3、6、12 mg·kg^-1)的主要药动学参数分别为:t_1/2Ke:6.03、6.24、6.89h;t_peak:3.83、3.83、4.67h;C_max:3.84、8.31、12.69 mg·L^-1;AUC_0-24:48.67,91.02,145.10 mg·L^-1·h。经检验,除C_max和AUC外,AA大鼠三个剂量组的药动学参数之间差异无统计学意义,C_max和AUC值与剂量成正比。3.单次给药结果表明,健康志愿者口服艾拉莫德25mg、50mg、75mg后,其T_1/2分别为8.55±3.01,6.31±3.15和7.30±2.94 h;T_max分别为3.38±0.92,4.88±1.96和4.33±1.00 h;Cmax分别为1.24±0.22,2.13±0.54和3.59±0.67 mg·L^-1;AUC分别为20.93±4.24,34.89±10.02和56.81±8.02 mg·L^-1·h。多次给药结果表明,健康志愿者口服艾拉莫德25mg后,T_1/2为10.25±7.17 h;T_max为3.63±1.60 h;C_max分别为1.88±0.31mg·L^-1;AUC为31.88±4.52 mg·L^-1·h。进食后给予艾拉莫德50mg后,试验组与对照组T_1/2分别为6.12±1.98、7.21±3.42h;T_max分别为3.53±1.14、4.35±1.79h;C_max分别为2.49±0.55、2.11±0.48 mg·L^-1;AUC_0-t分别为36.38±9.89、33.41±7.76 mg·L^-1·h,AUC_0-8分别为40.50±10.90、37.57±8.62 mg·L^-1·h。进食对艾拉莫德生物利用度影响的结果表明,F为107.67%,F’为106.45%。结论:1.本实验建立的HPLC检测大鼠和健康志愿者血清中艾拉莫德的方法稳定性好,灵敏度高,有一定重复性,符合生物样品分析要求。2.艾拉莫德在正常和AA大鼠体内的药动学参数比较,之间差异无统计学意义。3.单次给药时,三个剂量之间的Cmax,AUC参数呈线性关系;连续给药时,T_1/2、T_max和Cmax与单次给药的T_1/2、T_max和Cmax比较,之间差异无统计学意义。经配对t检验,连续给药与单次给药的AUC值比较差异有显著性（P＜0.05）。进食后口服药物可使艾拉莫德在人体内的达峰浓度升高,缩短药物的达峰时间。更多还原

【Abstract】 Objective:Iguratimod（N-[7-[（Methanesulfonyl）amino]-4-oxo-6-phenoxy-4H- 1-benzopyran -3-yl]formamide）,is a kind of non-storoidal anti-inflammtory drugs（NSAIDs）.It not only can selectively inhibit cycloxygenase-2（COX-2）,but also has immune regulatory effect. Iguratimod has better therapeutic efficacy and less adverse drug reaction than that of same class drugs.The clinical pharmacological characteristics of iguratimod in treatment of rheumatoid arthritis（RA） are as following:taking effect rapidly,alleviating the inflammation swelling,meliorating pain and improving function.Literatures reported that the anti-inflammatory and analgesic property of iguratimod was through its effect of selectively inhibiting COX-2,then reducing the production of prostaglandin （PGs） in inflammatory tissues.Although many researches were focused on the pharmacological effects of iguratimod,the pharmacokinetics characteristic of iguratimod for animals or human is still not clear.In this study,adjuvant arthritis rats were induced and administered iguratimod intragastricly.Meanwhile,recruited healthy volunteers were asked to administer iguratimod single or multiple times or after food.The concentration of iguratimod in serum was determined by high performance liquid chromatography, （HPLC）.The pharmacokinetics parameters such as T_max、C_max、t_1/2、area under curve（AUC） was calculated by DAS software.This research will provide experimental basis for the reasonable application of iguratimod in clinical.Methods:The method of analyzing iguratimod in serum of rats or human by HPLC was established.Rats received repeated administration of iguratimod,including normal group(6mg·kg^-1) and modeling groups(3、6、12mg·kg^-1 three groups).Healthy volunteers received single one time and three doses（25,50 or 75 mg） or multiple time and single dose（25 mg） or one time and single dose（50 mg） after food.Serum concentration of igurattimod was measured by HPLC.The concentration of iguratimod in the samples was determined by HPLC method.The pharmacokinetics parameters were calculated with DAS software.Result:1.In the chromatogram,the peaks of iguratimod in serum of rats or human and internal standard can separate from impurity peaks completely.The method has good specificity.The limit of detection for iguratimod was 0.10 mg·L^-1.The linearity range of iguratimod in serum of rats and human were 0.28-18 mg·L^-1 and 0.10-10 mg·L^-1 respectively.The relative recoveries were more than 90%and the relative standard deviation of the intra-day and inter-day were less than 5%.2.The main pharmacokinetics parameters such as t_1/2Ke,t_peak,C_max and AUC_0-24 of normal group(6 mg·kg^-1) were 3.56h,4.00h,8.87 mg·L^-1and 74.76 mg·L^-1·h respectively.The main pharmacokinetics parameters such as t_1/2Ke,t_peak,C_max and AUCo-24 of model groups(3 mg·kg^-1) were 4.54 h,3.83 h,3.84 mg·L^-1 and 40.21 mg·L^-1.h;the t_1/2Ke,t_peak,C_max and AUC_0-24 of model groups(6 mg·kg^-1 ) were 3.20 h,3.83 h,8.31 mg·L^-1 and 76.72 mg·L^-1.h;the t_1/2Ke,t_peak,C_max and AUC_0-24 of model groups(12 mg·kg^-1) were 3.17h,4.67h,12.69 mg·L^-1 and 117.06 mg·L^-1·h. Except C_max and AUC,no significant differences were found between the three model groups.3.The t_1/2 of 25,50 and 75 mg in single time and three doses of iguratimod were 8.55±3.01 h,6.31±3.15 h and 7.30±2.94h respectively.The T_max of 25,50 and 75 mg was 3.38±0.92 h,4.88±1.96 h and 4.33±1.00h respectively.The C_max of 25,50 and 75 mg was 1.24±0.22 mg·L^-1,2.13±0.54 mg·L^-1 and 3.59±0.67 mg·L^-1 respectively. AUC was 20.93±4.24 mg·L^-1.h,34.89±10.02 mg·L^-1·h and 56.81±8,02 mg·L^-1·h. respectively.In multiple times and single dose（25 mg） of iguratimod,the t_1/2,T_max, C_max and AUC was 10.25±7.17h,3.63±1.60h,1.88±0.31mg·L^-1 and 31.88±4.52mg·L^-1·h respectively.In the experiment of food intake,the t_1/2 of the two groups were 6.12±1.98 h and 7.21±3.42h,the T_max of the two groups were3.53±1.14 h and 4.35±1.79h,the C_max were 2.49±0.55 mg·L^-1 and 2.11±0.48 mg·L^-1,the AUC were36.38±9.89 mg·L^-1·h and 33.41±7.76 mg·L^-1·h,and the AUC_0-8 of the two groups were 40.50±10.90 mg·L^-1·h and 37.57±8.62 mg·L^-1·h respectively.Conclusion:1.The method established in this experiment has a good repeatablity and stability which fit to the requirement of analysis with biological specimen.2.The main pharmacokinetics parameters between normal rats and AA rats were compared,there were no significant differences.3.Cmax and AUC exhibited linear kinetics in single time and three doses of iguratimod. The pharmacokinetics parameters such as T_1/2,T_max and C_max between single time and multiple times were compared,there were no significant differences.While there were significant differences between the two groups for AUC.Food intake before administration may increase the C_max and shorten the T_max of igutimod in human.更多还原