Ion-trapping, microsomal binding, and unbound drug distribution in the hepatic retention of basic drugs

Siebert, Gerhard A., Hung, Daniel Y., Chang, Ping and Roberts, Michael S. (2004) Ion-trapping, microsomal binding, and unbound drug distribution in the hepatic retention of basic drugs. Journal of Pharmacology And Experimental Therapeutics, 308 1: 228-235. doi:10.1124/jpet.103.056770

Author Siebert, Gerhard A.
Hung, Daniel Y.
Chang, Ping
Roberts, Michael S.
Title Ion-trapping, microsomal binding, and unbound drug distribution in the hepatic retention of basic drugs
Journal name Journal of Pharmacology And Experimental Therapeutics   Check publisher's open access policy
ISSN 0022-3565
Publication date 2004
Sub-type Article (original research)
DOI 10.1124/jpet.103.056770
Volume 308
Issue 1
Start page 228
End page 235
Total pages 8
Editor S. J. Enna
L. LeCount
Place of publication USA
Publisher American Society for Pharmacology and Experimental Therapeutics (ASPET)
Collection year 2004
Language eng
Subject C1
320503 Clinical Pharmacology and Therapeutics
730118 Organs, diseases and abnormal conditions not elsewhere classified
Abstract This study investigated the relative contribution of ion-trapping, microsomal binding, and distribution of unbound drug as determinants in the hepatic retention of basic drugs in the isolated perfused rat liver. The ionophore monensin was used to abolish the vesicular proton gradient and thus allow an estimation of ion-trapping by acidic hepatic vesicles of cationic drugs. In vitro microsomal studies were used to independently estimate microsomal binding and metabolism. Hepatic vesicular ion-trapping, intrinsic elimination clearance, permeability-surface area product, and intracellular binding were derived using a physiologically based pharmacokinetic model. Modeling showed that the ion-trapping was significantly lower after monensin treatment for atenolol and propranolol, but not for antipyrine. However, no changes induced by monensin treatment were observed in intrinsic clearance, permeability, or binding for the three model drugs. Monensin did not affect binding or metabolic activity in vitro for the drugs. The observed ion-trapping was similar to theoretical values estimated using the pHs and fractional volumes of the acidic vesicles and the pK(a) values of drugs. Lipophilicity and pK(a) determined hepatic drug retention: a drug with low pK(a) and low lipophilicity (e.g., antipyrine) distributes as unbound drug, a drug with high pK(a) and low lipophilicity (e.g., atenolol) by ion-trapping, and a drug with a high pK(a) and high lipophilicity (e.g., propranolol) is retained by ion-trapping and intracellular binding. In conclusion, monensin inhibits the ion-trapping of high pK(a) basic drugs, leading to a reduction in hepatic retention but with no effect on hepatic drug extraction.
Keyword Perfused-rat-liver
Lysosomotropic Agents
Tissue Distribution
Intracellular Ph
Dispersion Model
Pharmacology & Pharmacy
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
2005 Higher Education Research Data Collection
School of Medicine Publications
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 46 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 52 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Wed, 15 Aug 2007, 03:30:39 EST