School of Pharmacy, Curtin University and Curtin Health Innovation Research Institute, Perth, Western Australia, Australia.
J Pharmacol Sci. 2010;113(4):315-24. doi: 10.1254/jphs.10109fp.
This study was conducted to determine the rate of P-glycoprotein (P-gp)-mediated efflux of digoxin analogues and metabolites and to assess the effects of macrolide antibiotics on this efflux. Bidirectional transport studies were conducted using our Caco-2 sub clone with high P-gp expression (CLEFF9). HPLC methods were employed to measure drug transport. All digoxin metabolites were P-gp substrates, although digoxin had the greatest efflux ratio. Erythromycin had no effect on the transport of digoxin, maintaining a basolateral to apical efflux ratio of 14.8, although it did reduce the efflux ratio of dihydrodigoxin and digoxigenin by 34% and 43%, respectively. Azithromycin also had little effect on the transport of digoxin or any of its metabolites. In contrast, clarithromycin and roxithromycin almost eliminated basolateral targeted efflux. Using paclitaxel as a known P-gp substrate, erythromycin demonstrated only partial P-gp inhibitory capacity, maintaining an efflux ratio over 100. In contrast, clarithromycin and roxithromycin were 10-fold greater P-gp inhibitors. Clarithromycin and roxithromycin are likely to exhibit drug interactions with digoxin via inhibition of efflux mechanisms. Azithromycin appears to have little influence on P-gp-mediated digoxin absorption or excretion and would be the safest macrolide to use concurrently with oral digoxin.
本研究旨在确定地高辛类似物和代谢物的 P-糖蛋白 (P-gp) 介导外排率，并评估大环内酯类抗生素对此外排的影响。使用我们具有高 P-gp 表达（CLEFF9）的 Caco-2 亚克隆进行了双向转运研究。采用 HPLC 方法测量药物转运。所有地高辛代谢物均为 P-gp 底物，尽管地高辛的外排率最高。红霉素对地高辛的转运没有影响，维持基底外侧到顶端的外排率为 14.8，尽管它分别将二氢地高辛和地高辛配基的外排率降低了 34%和 43%。阿奇霉素对地高辛或其任何代谢物的转运也几乎没有影响。相比之下，克拉霉素和罗红霉素几乎消除了基底外侧靶向外排。用紫杉醇作为已知的 P-gp 底物，红霉素仅表现出部分 P-gp 抑制能力，维持超过 100 的外排率。相比之下，克拉霉素和罗红霉素是 10 倍更强的 P-gp 抑制剂。克拉霉素和罗红霉素可能通过抑制外排机制与地高辛发生药物相互作用。阿奇霉素似乎对地高辛的 P-gp 介导吸收或排泄影响不大，与口服地高辛同时使用时是最安全的大环内酯类药物。
