罗红霉素胶囊在人体内的药动学及生物等效性研究

Study on Pharmacokinetics and Bioequivalence of Roxithromycin

目的建立人血浆中罗红霉素浓度的HPLC-MS分析方法,用以测定健康受试者口服罗红霉素制剂后的血药浓度,估算受试制剂和参比制剂的药动学参数,评价两种制剂的生物等效性和相对生物利用度.方法血浆中加入内标克拉霉素后,乙醚提取,HPLC-MS分离、分析.色谱系统：汉邦ODS柱（4.6 mm×150 mm）,甲醇-醋酸铵溶液（0.01 mol·L^-1）（75：25）为流动相,流速1.0 mL·min^-1,柱温35℃.质谱检测方式：SIM.结果罗红霉素的线性范围为0.1～15 mg·L^-1（r=0.999 9）,最低检测浓度达0.01 mg·L^-1,提取回收率≥80%.受试制剂及参比制剂的生物半衰期分别为（11.40±2.07）和（11.16±2.05）h,达峰时间分别为（2.7±0.8）和（2.9±0.9）h,峰浓度分别为（6.45±2.58）和（5.94±1.61）mg·L^-1.受试制剂的相对生物利用度为（102.6±17.4）%.结论本法简便,准确,灵敏度高.统计学结果表明,两种制剂具有生物等效性.

OBJECTIVE To establish a HPLC-MS method for the determination of pharmacokinetics and bioequivalence of roxithromycin in human body.METHODS Clarithromycin was used as internal standard. After adding clarithromycin, the plasma samples were extracted with ether and determined by HPLC-MS. The separation was carried out on a Hanbang ODS column （4.6 mm× 150 mm,packed with 5 μn C18 silica RP particle） at 35 ℃ .The mobile phase consisted of methanol -0.01 mol· L^-1 ammonium acetate （75：25）, at a flow ,ate of 1.0 mL· min^-1 .HPLC-MS was performed with the selected ion monitoring （SIM） mode using target ions at m/z 837.4 for roxithromycin and m/z 748.5 for elarithromycin. A randomized crossover design was performed in 20 healthy vohmteers. In the two study periods, a single dose of 150 mg was administered to each volunteer. RESULTS The linear calibration curve was obtained in the range of 0.1 - 15 mg· L^- 1 （ r = 0.999 9）. The detection limit of roxithromycin in plasma was 0.01 mg·L^- 1. The average recovery was more than 80%. The parameters （ρmax） of roxithromycin in blood for the test and reference formulations were （6.45 ± 2.58） and （5.94 ± 1.61） mg· L^- 1, at （2.7 ± 0.8） and （2.9 ± 0.9） h, respectively. Parameters of hi2 were （11.40 ± 2.07） and （ 11.16 ± 2.05） h, respectively. The relative bioavailability of the test formulation was （ 102.6 ± 17.4） %. CONCLUSION The assay is proved to be sensitive, accurate and convenient. The two formulations are bioequivalent.