目的 研究美敏伪麻缓释胶囊经单、多次给药后的药动学特征, 评估其在健康志愿者体内的安全性。方法 22例受试者随机、开放试验设计, 研究单、多次给药药动学特征。血浆中氯苯那敏、伪麻黄碱、右美沙芬、右啡烷采用LC-MS/MS法测定, 药动学参数采用WinNonlin软件计算。安全性特征以记录到的所有不良事件来进行评价。结果 整个研究过程中没有严重不良事件报告。单次口服美敏伪麻缓释胶囊后, 伪麻黄碱、氯苯那敏、右美沙芬和右啡烷均在3~5 h达峰, t_1/2分别为6.30±1.17、23.3±6.91、10.4±2.19、8.62±3.04 h, C_max分别为203±40.4、5.05±1.39、4.29±3.95、1.95±0.72 ng/mL, AUC_last分别为2 050±559、137±47.5、61.3±67.5、17.2±6.58 μg∙h/L, AUC_inf分别为2 140±570、161±63.8、17.6±6.65、62.8±69.3 μg∙h/L。在2次/d, 连续给药4 d后基本达到稳态血药浓度, 伪麻黄碱、氯苯那敏、右美沙芬和右啡烷的C_max、C_min、AUC_{tau, ss}与单次给药比较均有不同程度的升高, 波动系数的平均值为107%~271%。结论 美敏伪麻缓释胶囊多次给药后4 d达到稳态血药浓度, 暴露均较单次给药后有所增高, 在健康志愿者体内安全性良好。

Objective To investigate pharmacokinetics of Dextromethorphan Chlorpheniramine Pseudoephedrine Controlled-release Capsule after single and multiple doses, and make an assessment on the security in healthy volunteers. Methods Random and open trial was carried out for 22 healthy volunteers. A single and multiple oral dose of Dextromethorphan Chlorpheniramine Pseudoephedrine Controlled-release Capsule were given. The concentrations of dextromethorphan, chlorpheniramine, pseudoephedrine, and dextrorphan in plasma were determined by LC-MS/MS method. Pharmacokinetic parameters were calculated using WinNonlin program. Safety was evaluated using observed adverse events. Results No observed severe adverse event was reported. For chlorpheniramine, pseudoephedrine, dextromethorphan, and dextrorphan, median of t_max were about 3.0 — 5.0 h, means of t_1/2 were 6.30 ± 1.17, 23.3 ± 6.90, 10.4 ± 2.19, and 8.62 ± 3.04 h. Means of C_max were 203 ± 40.4, 5.05 ± 1.39, 4.29 ± 3.95, and 1.9 5 ± 0.720 ng/mL. Means of AUC_last were 2 055 ± 559, 137 ± 47.5, 61.3 ± 67.5, and 17.2 ± 6.58. Means of AUC_inf were 2 140 ± 570, 161 ± 63.8, 17.6 ± 6.65, and 62.8 ± 69.3μg∙h/L after single dose. After four-day continuous dosing, steady status was reached for all compounds. Their C_max, C_min, and AUC_{tau, ss} increased by different extent, and FI were within the range of 107% — 271%. Conclusion Dextromethorphan Chlorpheniramine Pseudoephedrine Controlled-release Capsule reaches steady status after four-day continuous doses, plasma exposures of four compounds increase than those after single dose, and capsule are well tolerated in healthy volunteers.

国家自然科学基金资助项目(81403013);国家科技重大专项(2012ZX09303006-002);北京协和医院中青年基金资助项目(pumch-2013-118)