Inhibition of P-glycoprotein-mediated efflux of digoxin and its metabolites by macrolide antibiotics

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. © 2010 the japanese pharmacological society.