title: Inhibition of P-glycoprotein-mediated efflux of digoxin and its metabolites by macrolide antibiotics.
abstract: 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.
authors: School of Pharmacy, Curtin University and Curtin Health Innovation Research Institute, Perth, Western Australia, Australia.
authors: Jeff
authors: J
authors: Hughes
authors: Andrew
authors: A
authors: Crowe
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D018938:Caco-2 Cells; D002851:Chromatography, High Pressure Liquid; D004077:Digoxin / Q000493:pharmacokinetics*; D006801:Humans; D057230:Limit of Detection; D018942:Macrolides / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000900:Anti-Bacterial Agents; D018942:Macrolides; D004077:Digoxin