Inhibition of P-glycoprotein–Mediated Efflux of Digoxin and Its Metabolites by Macrolide Antibiotics

Journal of Pharmacological Sciences

Jeff Hughes¹  Andrew Crowe¹ 

[1] School of Pharmacy, Curtin University and Curtin Health Innovation Research Institute (CHIRI), Australia

关键词: azithromycin;    erythromycin;    clarithromycin;    P-glycoprotein;    Caco-2;   

DOI  :  10.1254/jphs.10109FP

学科分类：药学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(40)Cited-By(23)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.

【 授权许可】

Unknown