Pharmaceutical Sciences, PharmaTherapeutics, Pfizer Global R&D, MS-4124, Groton, Connecticut 06340, USA.
Pharm Res. 2010 Jul;27(7):1361-6. doi: 10.1007/s11095-010-0126-6. Epub 2010 Apr 6.
Azithromycin capsules are known to exhibit a negative food effect, manifest as a decrease in azithromycin bioavailability in the fed state. Azithromycin tablets are known to be bioequivalent to capsules in the fasted state, but do not exhibit a food effect. In the present study, the involvement of gastric degradation of azithromycin to des-cladinose azithromycin (DCA) has been investigated as a possible mechanism for the observed capsule food effect.
Healthy volunteers were dosed with azithromycin tablets and capsules, fasted and fed, in a four-way randomized crossover study. Serum levels of DCA were measured as a function of time post-dose. Natural log-transformed PK parameters were statistically analyzed using an ANOVA model appropriate for the study design.
When capsules were dosed to fed subjects, the systemic AUC for DCA was 243% of the value observed after fasted-state dosing, and the DCA C(max) was 270% of the value observed after fasted-state dosing. When azithromycin tablets were dosed in the fasted and fed states, there was no significant difference in systemic DCA.
Gastric degradation of azithromycin to DCA is the likely mechanism for the observed negative food effect observed for azithromycin capsules. This effect is not observed for tablets. These observations suggest that azithromycin capsules exhibit slow and/or delayed disintegration in the fed stomach, resulting in extended gastric residence and degradation of a portion of the gastrically retained azithromycin.
已知阿奇霉素胶囊具有负食物效应，表现在进食状态下阿奇霉素生物利用度降低。已知阿奇霉素片剂在空腹状态下与胶囊生物等效，但不表现出食物效应。在本研究中，研究了阿奇霉素在胃中降解为去克拉定糖阿奇霉素（DCA）可能是观察到胶囊食物效应的机制。
在一项四交叉随机交叉研究中，健康志愿者空腹和进食时分别服用阿奇霉素片剂和胶囊。作为时间的函数，测量血清 DCA 水平。使用适合研究设计的 ANOVA 模型对自然对数转化后的 PK 参数进行统计分析。
当胶囊给进食受试者服用时，DCA 的全身 AUC 是空腹状态下给药后观察到的值的 243%，DCA 的 C(max)是空腹状态下给药后观察到的值的 270%。当在空腹和进食状态下给予阿奇霉素片剂时，系统 DCA 没有显著差异。
阿奇霉素在胃中降解为 DCA 是阿奇霉素胶囊观察到的负食物效应的可能机制。片剂没有这种作用。这些观察结果表明，阿奇霉素胶囊在进食胃中表现出缓慢和/或延迟崩解，导致胃滞留时间延长和部分胃内滞留的阿奇霉素降解。
