苯佐那酯软胶囊在中国健康受试者中的药代动力学研究  

Pharmacokinetics of Benzonatate Soft Capsules in Chinese Healthy Volunteers

作　　者：满珈羽 焦菲菲 王逸雅 顾月清[1] 舒畅[1] 丁黎[1,2] MAN Jiayu;JIAO Feifei;WANG Yiya;GU Yueqing;SHU Chang;DING Li(China Pharmaceutical University,Nanjing 210009,China;Nanjing Clinical Tech. Laboratories Inc.,Nanjing 211100,China)

机构地区：[1]中国药科大学,南京210009 [2]南京科利泰医药科技有限公司,南京211100

出　　处：《药学与临床研究》2019年第4期241-245,共5页Pharmaceutical and Clinical Research

基　　金：国家自然科学基金(81573387、81603072);双一流大学项目(CPU2018GY24)

摘　　要：目的:研究中国健康受试者口服苯佐那酯软胶囊后苯佐那酯及其代谢产物4-N-丁基氨基苯甲酸(BBA)的药代动力学特征。方法:36名健康受试者分为A、B、C 3组,A、C组分别单次口服苯佐那酯软胶囊100 mg(低)、400 mg(高),B组单次及多次口服苯佐那酯软胶囊200 mg(中)。通过HPLC-MS/MS法检测血浆中BBA的浓度,推算血浆中苯佐那酯的浓度,估算药代动力学参数。结果:A、B、C 3组受试者单次给药苯佐那酯软胶囊后,BBA的Tmax分别为(0.74±0.40)、(0.54±0.24)、(0.61±0.43) h,Cmax分别为(1 603±443)、(2 833±1131)、(6 549±2 009) ng·mL^-1,AUC0-10h分别为(2 395±1 062)、(3 403±1 228)、(9 104±4 134) ng·h·mL^-1,t1/2分别为(1.42±0.52)、(1.84±0.89)、(1.70±0.75) h;苯佐那酯的Tmax分别为(0.62±0.25)、(0.62±0.27)、(0.58±0.37) h,Cmax分别为(1 201± 449)、(1 838±700)、(3 554±1 775) ng·mL^-1,AUC0-10h分别为(1 314±589)、(1 751±656)、(3 452± 2 111) ng·h·mL^-1,t1/2分别为(1.57±1.17)、(1.80±1.05)、(1.68±1.04) h。B组受试者多次给药苯佐那酯软胶囊200 mg后,BBA的Cav为(604±220) ng·mL^-1,DF为(5.34±1.26),RCmax为(1.20±0.45),RAUC为(1.10±0.13);苯佐那酯的Cav为(356±126) ng·mL^-1,DF为(5.91±1.35),RCmax为(1.24±0.57),RAUC为(1.31±0.33)。结论:在100~400 mg的给药剂量范围内,苯佐那酯不具有线性药代动力学特征。多次给药苯佐那酯软胶囊200 mg后,BBA和苯佐那酯在体内会产生蓄积。Objective:To study the pharmacokinetics of benzonatate and its metabolite 4-(butylamino)benzoic acid (BBA) after oral administration of benzonatate soft capsules in Chinese healthy volunteers.Methods:Thirty-six volunteers were divided into A,B and C groups.Volunteers in group A or group C took benzonatate soft capsules orally at a single dose of 100 mg or 400 mg,respectively.Volunteers in group B took benzonatate soft capsules at single and multiple doses of 200 mg.The concentrations of BBA in plasma were detected by HPLC-MS/MS.The concentrations of benzonatate in plasma were extrapolated based on the concentrations of BBA.The pharmacokinetic parameters were evaluated accordingly.Results:After oral administration of benzonatate soft capsules at a single dose of 100 mg,200 mg or 400 mg,respectively,the Tmax of BBA were (0.74 ± 0.40),(0.54 ± 0.24) or (0.61 ± 0.43) h;the Cmax were (1 603 ± 443),(2 833 ± 1 131) or (6 549 ± 2 009) ng·mL^-1;the AUC0-10h were (2 395 ± 1 062),(3 403 ± 1 228) or (9 104 ± 4 134) ng·h·mL^-1;and the t1/2 were (1.42 ± 0.52),(1.84 ± 0.89) or (1.70 ± 0.75) h.For benzonatate as extrapolated,respectively,the Tmax were (0.62 ± 0.25),(0.62 ± 0.27) or (0.58 ± 0.37) h;the Cmax were (1 201 ± 449),(1 838 ± 700) or (3 554 ± 1 775) ng·mL^-1;the AUC0-10h were (1 314 ± 589),(1 751 ± 656) or (3 452 ± 2 111) ng·h·mL^-1;the t1/2 were (1.57 ± 1.17),(1.80 ± 1.05) or (1.68 ± 1.04) h.After oral administration of benzonatate soft capsules at multiple doses of 200 mg,the Cav,DF,RCmax and RAUC of BBA were (604 ± 220) ng·mL^-1,(5.34 ± 1.26),(1.20 ± 0.45) and (1.10 ± 0.13),respectively.The Cav,DF,RCmax and RAUC of benzonatate were (356 ± 126) ng·mL^-1,(5.91 ± 1.35),(1.24 ± 0.57) and (1.31 ± 0.33),respectively as extrapolated.Conclusions:Benzonatate has non-linear pharmacokinetic characteristics in the dose range of 100 mg to 400 mg.BBA and benzonatate will accumulate after multiple doses of 200 mg.

关 键 词：苯佐那酯 4-N-丁基氨基苯甲酸 聚合物 HPLC-MS/MS 药代动力学 

分 类 号：R969.1[医药卫生—药理学]