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Decreased biliary excretion of tributylmethyl ammonium in cholestyramine pretreated rats due to reduced formation of ion‐pair complexes with hepatic bile salts
Author(s) -
Choi M. K.,
Song I. S.,
Kim D. D.,
Chung S. J.,
Shim C. K.
Publication year - 2007
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.580
Subject(s) - cholestyramine , chemistry , medicine , excretion , endocrinology , ammonium , bile acid , sulfobromophthalein , salt (chemistry) , liver function tests , biochemistry , cholesterol , organic chemistry
The hypothesis that higher molecular weight (MW) quaternary ammoniums (QAs) form lipophilic ion‐pair complexes with bile salts in the liver, and are subsequently excreted into bile via a canalicular transporter, P‐gp, was re‐examined in the present study for its validity. The biliary excretion of tributylmethyl ammonium (TBuMA), a QA with a MW of 200, in bile salt‐depleted rats was determined. Depletion was induced by a daily oral administration of a resin, cholestyramine, at a dose of 0.5 g/kg for 2 consecutive weeks, which decreased the concentration of total bile salts in the liver by 38%. When TBuMA was administered intravenously (12 µmol/kg) to these rats, the plasma level, area under the plasma concentration‐time curve ( AUC ), systemic clearance ( CL ) and volume of distribution ( V ss ) of the compound remained unchanged, whereas bile flow (23.03 vs 16.94 µl/min, p <0.05) and biliary clearance ( CL bile , 12.75 vs 5.34 ml/min/kg, p <0.01) were decreased significantly. These results implied the biliary clearance of TBuMA in rats with bile salt depletion was significantly decreased as a result of decreased ion‐pair complexation of TBuMA. The above results are consistent with our hypothesis and the existence of a MW threshold (i.e. 200±50 for rats) for the biliary excretion of QAs. Copyright © 2007 John Wiley & Sons, Ltd.