title: Effect of macrolide antibiotics on uptake of digoxin into rat liver.
abstract: The objective of this study was to examine the effect of macrolide antibiotics, clarithromycin, erythromycin, roxithromycin, josamycin and azithromycin, on the hepatic uptake of digoxin. The uptake of [(3)H]digoxin was studied in rats in vivo, using the tissue-sampling single-injection technique, and in isolated rat hepatocytes in vitro. The uptake of [(3)H]digoxin into rat hepatocytes was concentration-dependent with a Michaelis constant (K(m)) of 445 nM. All the macrolide antibiotics inhibited the uptake of [(3)H]digoxin into rat hepatocytes in a concentration-dependent manner. However, clarithromycin did not affect the in vivo hepatic uptake of digoxin in rats. The in vivo permeability-surface area product of digoxin for hepatic uptake (PS(inf)) was estimated to be 12.5 ml/min/g liver from the present in vitro data, which is far larger than the hepatic blood flow rate (1.4 ml/min/g liver). Macrolide antibiotics at clinically relevant concentrations inhibit digoxin uptake by rat hepatocytes in vitro, but not in vivo, probably because hepatic uptake of digoxin in rats is blood flow-limited. Clinically observed digoxin-macrolide interaction in humans could be due to macrolide inhibition of hepatic digoxin uptake, if the uptake is permeation-limited.
authors.affiliation: Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka-shi, Fukuoka 812-8582, Japan.
authors.forename: Suwako
authors.initials: S
authors.lastname: Ito
authors.forename: Risa
authors.initials: R
authors.lastname: Nasu
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tsujimoto
authors.forename: Hideyasu
authors.initials: H
authors.lastname: Murakami
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Ohtani
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Sawada
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017963:Azithromycin / Q000494:pharmacology; D001692:Biological Transport; D001783:Blood Flow Velocity; D002316:Cardiotonic Agents / Q000493:pharmacokinetics*; D017291:Clarithromycin / Q000494:pharmacology; D004077:Digoxin / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004917:Erythromycin / Q000494:pharmacology; D022781:Hepatocytes / Q000378:metabolism; D015570:Josamycin / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology*; D008297:Male; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D015575:Roxithromycin / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: D000900:Anti-Bacterial Agents; D002316:Cardiotonic Agents; D018942:Macrolides; D015575:Roxithromycin; D004917:Erythromycin; D004077:Digoxin; D017963:Azithromycin; D017291:Clarithromycin; D015570:Josamycin