Kinetic analysis of saturable hepatic uptake of digoxin and its inhibition by rifampicin

Weiss, Michael, Hung, Daniel Y., Poenicke, Klaus and Roberts, Michael S. (2008) Kinetic analysis of saturable hepatic uptake of digoxin and its inhibition by rifampicin. European Journal of Pharmaceutical Sciences, 34 4-5: 345-350. doi:10.1016/j.ejps.2008.05.007


Author Weiss, Michael
Hung, Daniel Y.
Poenicke, Klaus
Roberts, Michael S.
Title Kinetic analysis of saturable hepatic uptake of digoxin and its inhibition by rifampicin
Journal name European Journal of Pharmaceutical Sciences   Check publisher's open access policy
ISSN 0928-0987
1879-0720
Publication date 2008-08-07
Year available 2008
Sub-type Article (original research)
DOI 10.1016/j.ejps.2008.05.007
Open Access Status Not yet assessed
Volume 34
Issue 4-5
Start page 345
End page 350
Total pages 6
Editor A. Urtti
Place of publication Amsterdam, Netherlands
Publisher Elseiver
Language eng
Subject 970111 Expanding Knowledge in the Medical and Health Sciences
111502 Clinical Pharmacology and Therapeutics
Abstract Although the organic anion transporter Oatp2 plays a critical role in determining the hepatic clearance ofsome drugs, little quantitative information exists about its functional characteristics in relation to inhibition of sinusoidal drug uptake. We investigated the uptake kinetics of the Oatp2 substrate digoxin in the isolated perfused rat liver. In the single-pass perfused liver three consecutive digoxin doses of 15, 30 and 45 tg were administered in the presence or absence of rifampicin (100 ItM), an inhibitor of Oatp2. Digoxin was determined in the outflow samples b HPLC and all data were a l d b i l y na yze y s mu taneous nonlinear regression assuming a Michaelis-Menten uptake mechanism. Hepatocellular uptake of digoxin was concentration -dependent with a Michaelis constant (Km) of 577.8ng/ml. Rifampicin significantly reduced uptake (Km increased 2.S-fold) without affecting other parameters. (c) 2008 Elsevier B.V. All rights reserved.
Formatted abstract
Although the organic anion transporter Oatp2 plays a critical role in determining the hepatic clearance of some drugs, little quantitative information exists about its functional characteristics in relation to inhibition of sinusoidal drug uptake. We investigated the uptake kinetics of the Oatp2 substrate digoxin in the isolated perfused rat liver. In the single-pass perfused liver three consecutive digoxin doses of 15, 30 and 45 μg were administered in the presence or absence of rifampicin (100 μM), an inhibitor of Oatp2. Digoxin was determined in the outflow samples by HPLC and all data were analyzed by simultaneous nonlinear regression assuming a Michaelis–Menten uptake mechanism. Hepatocellular uptake of digoxin was concentration-dependent with a Michaelis constant (KM) of 577.8 ng/ml. Rifampicin significantly reduced uptake (KM increased 2.5-fold) without affecting other parameters.
Keyword Hepatic uptake
Oatp2
Digoxin
Rifampicin
Rat liver
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2009 Higher Education Research Data Collection
Excellence in Research Australia (ERA) - Collection
School of Medicine Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 13 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 13 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Wed, 01 Apr 2009, 02:14:02 EST by Maree Knight on behalf of Faculty Of Health Sciences