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目的:建立 HPLC-MS 法测定阿奇霉素在血清中的浓度,以研究阿奇霉素在健康志愿者中的药代动力学和相对生物利用度。方法:20例健康男性志愿者进行二交叉试验,随机单剂量口服阿奇霉素片剂或胶囊,按设定时间采集肘静脉血;取血清0.5 mL,经0.5 mol·L~(-1)的氢氧化钠溶液0.1 mL 碱化和氯仿4 mL 萃取处理,采用 Kromasil C_8(5μm,4.6mm×250mm)色谱柱,流动相为乙腈-水(85:15),水中含5 mmol·L~(-1)甲酸铵和0.3%的三乙胺,HPLC-MS 内标(罗红霉素)选择性正离子检测法测定血清中阿奇霉素浓度。结果:HPLC-MS 法检测血清中阿奇霉素的最低检测限为2.5 ng·mL~(-1),在2.5～640 ng·mL~(-1)范围内线性关系良好,日内、日间 RSD 均小于6%。口服阿奇霉素片剂和胶囊500 mg 的主要药代动力学参数 t_(1/2)分别为(35.7±3.9)h 和(35.5±3.3)h,T_(max)分别为(2.30±0.25)h 和(2.25±0.30)h,C_(max)分别为(350.99±55.71)ng·mL~(-1)和(344.23±60.60)ng·mL~(-1),AUC_(0～120)分别为(3951.90±497.12)ng·mL~(-1)·h 和(3909.24±556.26)ng·mL~(-1)·h,AUC_(0～∞)分别为(4303.66±529.61)ng·mL~(-1)·h 和(4254.33±589.98)ng·mL~(-1)·h。结论:建立的 HPLC-MS 方法具有特异性强、灵敏度高的优点,测定结果可靠;统计分析表明2种剂型药物的主要药代动力学参数无显著性差异,为等效制剂。
Objective: To establish a HPLC-MS method for the determination of azithromycin in serum to study the pharmacokinetics and relative bioavailability of azithromycin in healthy volunteers. Methods: Twenty healthy male volunteers were randomized into two crossover trials. Randomized single-dose oral azithromycin tablets or capsules were used to collect elbow venous blood at a set time. 0.5 mL of serum was added to 0.5 mL of hydrogen peroxide 0.1 mL of sodium chloride solution and 4 mL of chloroform were used for the extraction. The mobile phase consisted of acetonitrile-water (85:15) with 5 mmol·L -1 of Kromasil C_8 (5 μm, 4.6 mm × 250 mm) The concentration of azithromycin in serum was determined by selective positive ion detection with ammonium formate and 0.3% triethylamine using HPLC-MS internal standard (roxithromycin). Results: The detection limit of azithromycin in serum was 2.5 ng · mL -1 by HPLC-MS, and the linearity was good in the range of 2.5-640 ng · mL -1. The intra-day and inter-day RSD were less than 6%. The main pharmacokinetic parameters of oral azithromycin tablets and capsules 500 mg t_ (1/2) were (35.7 ± 3.9) h and (35.5 ± 3.3) h, T max were (2.30 ± 0.25) h and (2.25 ± 0.30) h, and C max were (350.99 ± 55.71) ng · mL -1 and 344.23 ± 60.60 ng · mL -1, respectively. The AUC 0-120 values were ( 3951.9 ± 497.12 ng · mL -1 · h -1 and 3909.24 ± 556.26 ng · mL -1 · h -1 respectively, and the AUC 0 ~ ∞ were (4303.66 ± 529.61) ng · mL ~ (- 1) · h and (4254.33 ± 589.98) ng · mL -1 (-1) h. Conclusion: The established HPLC-MS method has the advantages of strong specificity and high sensitivity, and the determination result is reliable. The statistical analysis shows that the main pharmacokinetic parameters of the two dosage forms have no significant difference and are equivalent preparations.