Decreased biliary excretion of tributylmethyl ammonium in cholestyramine pretreated rats due to reduced formation of ion‐pair complexes with hepatic bile salts

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.