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

Study on pharmacokinetics and bioequivalence of different preparations of azithromycin in Beagle dogs

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:Gemini3μm,C6-Phenyl,100mm×3.00mm,100,流动相为0.1%甲酸水溶液-甲醇(30∶70),流速0.35mL·min-1,进样量5μL。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2.0g。结果:血浆标准曲线在0.05～10μg.mL-1范围内线性良好(r=0.9991),血浆中最低限量0.05μg.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Tmax分别为(3.17±2.70)h,(2.39±2.29)h,(0.50±0.22)h,Cmax分别为(3507.17±1811.27)μg.L-1,(3582.53±949.30)μg.L-1,(9668.10±3844.02)μg.L-1;t1/2分别为(56.01±23.07)h,(53.49±20.18)h,(44.29±12.07)h;用梯形法计算,AUC0-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;AUC0-∞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AUC0-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：Tmax（3.17±2.70）h,（2.39±2.29）h and（0.50±0.22）h,Cmax（3507.17±1811.27）μg·L-1,（3582.53±949.30）μg·L-1and（9668.10±3844.02）μg·L-1,t1/2（56.01±23.07）h,（53.49±20.18）h and（44.29±12.07）h;AUC0-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;AUC0-∞（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.