【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·m L-1,AUC0-10h分别为(2 395±1 062)、(3 403±1 228)、(9 104±4 134) ng·h·m L-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·m L-1,AUC0-10h分别为(1 314±589)、(1 751±656)、(3 452±2 111) ng·h·m L-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C-1av为(604±220) ng·m L,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·m L-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。更多还原

【Abstract】 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 Tmaxof BBA were(0.74 ± 0.40),(0.54 ± 0.24) or(0.61 ± 0.43) h; the Cmaxwere(1 603 ± 443),(2 833 ± 1 131) or(6 549 ± 2 009) ng·mL-1; the AUC0-10 hwere(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 Tmaxwere(0.62 ± 0.25),(0.62 ± 0.27) or(0.58 ± 0.37) h; the Cmaxwere(1 201 ± 449),(1 838 ±700) or(3 554 ± 1 775) ng·mL-1; the AUC0-10 hwere(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, RCmaxand RAUCof BBA were(604 ± 220) ng·mL-1,(5.34 ±1.26),(1.20 ± 0.45) and(1.10 ± 0.13), respectively. The Cav, DF, RCmaxand RAUCof 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.更多还原