Pharmacokinetics Study Of Iguratimod In Rat And Health Human

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.