阿莫西林克拉维酸钾干混悬剂在中国成年健康受试者的药代动力学研究

Pharmacokinetie study of amoxicillin potassium clavulanate dry suspension in adult healthy Chinese subjects

目的观察阿莫西林克拉维酸钾干混悬剂(阿莫西林400mg与克拉维酸57mg/5mL)于空腹及餐后状态下在中国健康受试者中的药代动力学(PK)特征。方法空腹试验与餐后试验各自入组36例中国健康成年受试者,本研究用单剂量、随机、开放性、两周期实验方案设计,每个周期中口服以水配制而成的受试制剂(或参比制剂)阿莫西林克拉维酸钾干混悬剂10mL,采集静脉血样,用液相色谱-串联质谱法测定人血浆中阿莫西林与克拉维酸钾的血药浓度,用PhoenixWinNonlin8.2软件非房室模型分析方法对血浆中2种有效成分的PK参数进行分析。结果空腹组阿莫西林的AUC_(0-∞)为(36.81±5.16)ug·mL^(-1)·h,AUC_(0-t)为(36.51±5.10)μg·mL^(-1)·h,C_(max)为(13.76±3.13)μg·mL^(-1),t_(1/2)为(1.42±0.16)h,t_(max)为1.25h;餐后组阿莫西林的AUC_(0-∞)为(39.65±5.86)μg·mL^(-1)h,AUC_(0-t)为(37.43±5.70)μg·mL^(-1)·h,C_(max)为(8.57±1.70)μg·mL^(-1),t_(1/2)为(1.77±0.57)h,tmx为3.25h。空腹组克拉维酸的AUC_(0-∞)为(5.01±2.05)μg·mL^(-1)·h,AUC_(0-t)为(4.973±2.05)μg·mL^(-1)·h,C_(max)为(2.05±0.87)μg·mL^(-1),t_(1/2)为(1.20±0.11)h,t_(max)为1.25h;餐后组克拉维酸的AUC_(0-∞)为(2.54±1.37)μg·mL^(-1)·h,AUC_(0-t)为(2.50±1.36)μg·mL^(-1)·h,C_(max)为(0.76±0.40)μg·mL^(-1),t_(1/2)为(1.13±0.16)h,t_(max)为2.50h。结论高脂高热量饮食后服药会显著降低克拉维酸的吸收速度及吸收程度,对阿莫西林的吸收及代谢无较大影响。

Objective To observe the pharmacokinetic profile of amoxicillin potassium clavulanate dry suspension(amoxicillin 400 mg with clavulanate 57 mg/5 mL)in fasting and fed states in healthy Chinese subjects.Methods Thirty-six healthy Chinese adult subjects were enrolled in each of the fasting and postprandial trials.A single-dose,randomized,open-ended,two-cycle experimental protocol was used in both groups,in which 10 mL of the test preparation(or the reference preparation),amoxicillin potassiumclavulanate,was administered orally with water in each cycle,and venous blood samples were collected for the determination of amoxicillin in human plasma using liquid chromatography-tandemmasssspectrometry.Theblood concentrations of amoxicillin and potassium clavulanate in human plasma were determined by liquid chromatography-tandem mass spectrometry(LC-MS/MS),and the pharmacokinetic(PK)parameters of the two active ingredients in the plasma were analyzed by the non-atrial modeling method using PhoenixWinNonlin 8.2 software.Results The pharmacokinetic parameters of the two main active ingredients were as follows:AUC_(0-∞)of amoxillin in the fasting group was(36.81±5.16)μg·mL^(-1).h;AUC_(0-t)was(36.51±5.10)μg mL^(-1).h;C_(max)was(13.76±3.13)μg·mL^(-1),t_(1/2)was(1.42±0.16)h;t_(max)was 1.25 h.AUC_(0-∞)for amoxicillin in the postprandial group was(39.65±5.86)μg·mL^(-1).h;AUC_(0-t)was(37.43±5.70)μg·mL^(-1).h;C_(max)was(8.57±1.70)μg·mL^(-1),t_(1/2)was(1.77±0.57)h;t_(max)was 3.25 h.AUC_(0-∞)of clavulanic acid in fasting group was(2.54±1.37)μg·mL^(-1).h;AUC_(0-t)was(4.97±2.05)μg·mL^(-1).h;C_(max)was(2.05±0.87)μg·mL^(-1);t_(1/2)was(1.20±0.11)h,t_(max)was 1.25 h.In the postprandial group clavulanic acid had an AUC_(0-∞)of(2.54±1.37)μg·mL^(-1).h;AUC_(0-t)was(2.50±1.36)μg·mL^(-1).h;Cmax was(0.76±0.40)μg·mL-l;t_(1/2)was(1.13±0.16)h;t_(max)was 2.50 h.Conclusion Taking the drug after a high-fat,high-calorie diet significantly reduced the rate and extent of clavulanic acid absorption,and had no major effect on the absorption and metabolism of amoxicillin.