Effect of macrolide antibiotics on uptake of digoxin into rat liver

Suwako Ito, Risa Nasu, Masayuki Tsujimoto, Hideyasu Murakami, Hisakazu Ohtani, Yasufumi Sawada

Research output: Contribution to journalArticle

8 Citations (Scopus)

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 [3H]digoxin into rat hepatocytes was concentration-dependent with a Michaelis constant (Km) of 445 nM. All the macrolide antibiotics inhibited the uptake of [3H]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 (PSinf) 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.

Original languageEnglish
Pages (from-to)113-123
Number of pages11
JournalBiopharmaceutics and Drug Disposition
Volume28
Issue number3
DOIs
Publication statusPublished - 2007 Apr
Externally publishedYes

Fingerprint

Digoxin
Macrolides
Anti-Bacterial Agents
Liver
Hepatocytes
Clarithromycin
Josamycin
Roxithromycin
Azithromycin
Erythromycin
Permeability
Injections

Keywords

  • Digoxin
  • Drug interaction
  • Hepatic uptake
  • Liver uptake index
  • Macrolide antibiotics

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Effect of macrolide antibiotics on uptake of digoxin into rat liver. / Ito, Suwako; Nasu, Risa; Tsujimoto, Masayuki; Murakami, Hideyasu; Ohtani, Hisakazu; Sawada, Yasufumi.

In: Biopharmaceutics and Drug Disposition, Vol. 28, No. 3, 04.2007, p. 113-123.

Research output: Contribution to journalArticle

Ito, Suwako ; Nasu, Risa ; Tsujimoto, Masayuki ; Murakami, Hideyasu ; Ohtani, Hisakazu ; Sawada, Yasufumi. / Effect of macrolide antibiotics on uptake of digoxin into rat liver. In: Biopharmaceutics and Drug Disposition. 2007 ; Vol. 28, No. 3. pp. 113-123.
@article{5dd553ae4c6f4be98bb461f523f229ce,
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 [3H]digoxin into rat hepatocytes was concentration-dependent with a Michaelis constant (Km) of 445 nM. All the macrolide antibiotics inhibited the uptake of [3H]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 (PSinf) 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.",
keywords = "Digoxin, Drug interaction, Hepatic uptake, Liver uptake index, Macrolide antibiotics",
author = "Suwako Ito and Risa Nasu and Masayuki Tsujimoto and Hideyasu Murakami and Hisakazu Ohtani and Yasufumi Sawada",
year = "2007",
month = "4",
doi = "10.1002/bdd.537",
language = "English",
volume = "28",
pages = "113--123",
journal = "Biopharmaceutics and Drug Disposition",
issn = "0142-2782",
publisher = "John Wiley and Sons Ltd",
number = "3",

}

TY - JOUR

T1 - Effect of macrolide antibiotics on uptake of digoxin into rat liver

AU - Ito, Suwako

AU - Nasu, Risa

AU - Tsujimoto, Masayuki

AU - Murakami, Hideyasu

AU - Ohtani, Hisakazu

AU - Sawada, Yasufumi

PY - 2007/4

Y1 - 2007/4

N2 - 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 [3H]digoxin into rat hepatocytes was concentration-dependent with a Michaelis constant (Km) of 445 nM. All the macrolide antibiotics inhibited the uptake of [3H]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 (PSinf) 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.

AB - 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 [3H]digoxin into rat hepatocytes was concentration-dependent with a Michaelis constant (Km) of 445 nM. All the macrolide antibiotics inhibited the uptake of [3H]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 (PSinf) 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.

KW - Digoxin

KW - Drug interaction

KW - Hepatic uptake

KW - Liver uptake index

KW - Macrolide antibiotics

UR - http://www.scopus.com/inward/record.url?scp=34248384071&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34248384071&partnerID=8YFLogxK

U2 - 10.1002/bdd.537

DO - 10.1002/bdd.537

M3 - Article

VL - 28

SP - 113

EP - 123

JO - Biopharmaceutics and Drug Disposition

JF - Biopharmaceutics and Drug Disposition

SN - 0142-2782

IS - 3

ER -