不同阿奇霉素制剂的Beagle犬体内药代动力学及其生物等效性研究

目的: 用LC/MS/MS方法研究受试制剂是否具有突释现象和缓释行为,并比较受试制剂和参比制剂的相对生物利用度。 方法: 阿奇霉素的血药浓度测定采用LC/MS/MS法测定,色谱柱:Gemini 3 μm,C₆-Phenyl,100 mm×3.00 mm,100 ,流动相为0.1%甲酸水溶液-甲醇(30∶ 70),流速0.35 mL·min^-1,进样量5 μL。9只Beagle犬口服受试制剂、参比制剂和阿奇霉素普通片剂,每只动物2.0 g。 结果: 血浆标准曲线在0.05~10 μg·mL^-1范围内线性良好(r=0.9991),血浆中最低限量0.05 μg·mL^-1,绝对回收率80.0%~95.5%,相对回收率94.6%~101.2%,日内、日间RSD小于10%。血浆中阿奇霉素的T_max分别为(3.17±2.70) h,(2.39±2.29) h,(0.50±0.22) h,C_max分别为(3507.17±1811.27) μg·L^-1,(3582.53±949.30) μg·L^-1,(9668.10±3844.02) μg·L^-1;t_1/2 分别为(56.01±23.07) h,(53.49±20.18) h,(44.29±12.07) h;用梯形法计算,AUC_0-t 分别为(67626.24±42712.70) μg·h·L^-1,(71198.01±19516.89) μg·h·L^-1,(60141.05±18383.66) μg·h·L^-1;AUC_0-∞分别为(86827.84±61174.14) μg·h·L^-1,(87291.59±27710.25) μg·h·L^-1,(69769.39±23170.33) μg·h·L^-1。以受试制剂和参比制剂的AUC_0-t计算,阿奇霉素的相对生物利用度平均为113.03%±41.60%(n=6)。 结论: 该法灵敏、准确,适合测定阿奇霉素血药浓度;受试制剂阿奇霉素缓释干混悬剂具有明显的缓释特征,与参比制剂相比,具有生物等效性。

Objective: With LC/MS/MS for plasma concentration,the test formulation had a slow-release,burst effect,and the relative bioavailability compared with the reference formulation. Method: Nine Beagle dogs were randomized into group three, the test formulation,the reference formulation and azithromycin tablets were given to them.Azithromycin plasma was determined by LC-MS/MS.The separation was achieved on C₆-Phenyl column (100 nm×3.00 mm,Gemini 3 μm) with aqueous solution (0.1% formic acid)-methanol (30∶ 70) as mobile phase. Results: The correlation coefficients of the calibration curves were better than 0.9991(n=6),in the range of 0.05-10 μg·mL^-1 for azithromycin.The absolute recoveries were 80.0%-95.5%,the relative recoveries were 94.6%-101.2%.The intra-day and inter-day RSDs were less than 10.0%.The pharmacokinetic parameters of the Beagle dogs after given 2 g azithromycin A/B/C were as follows:T_max(3.17±2.70)h,(2.39±2.29)h and (0.50±0.22)h,C_max (3507.17±1811.27)μg·L^-1,(3582.53±949.30) μg·L^-1and (9668.10±3844.02) μg·L^-1,t_1/2 (56.01±23.07)h,(53.49±20.18)h and (44.29±12.07)h;AUC_0-t (67626.24±42712.70) μg·h·L^-1,(71198.01±19516.89) μg·h·L^-1 and (60141.05±18383.66) μg·h·L^-1;AUC_0-∞(86827.84±61174.14) μg·h·L^-1,(87291.59±27710.25) μg·h·L^-1 and (69769.39±23170.33) μg·h·L^-1.The relative bioavailability of azithromycin A to azithromycin B was (113.03±41.60)%. Conclusion: The method for the determination of azithromycin plasma concentration is sensitive and accurate;the test is bioequivalent with the reference formul Lation.