title: Decreased biliary excretion of tributylmethyl ammonium in cholestyramine pretreated rats due to reduced formation of ion-pair complexes with hepatic bile salts.
abstract: 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 micromol/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 microl/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.
authors.affiliation: Research Institute of Pharmaceutical Sciences and Department of Pharmaceutics, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors.forename: M K
authors.initials: MK
authors.lastname: Choi
authors.forename: I S
authors.initials: IS
authors.lastname: Song
authors.forename: D D
authors.initials: DD
authors.lastname: Kim
authors.forename: S J
authors.initials: SJ
authors.lastname: Chung
authors.forename: C K
authors.initials: CK
authors.lastname: Shim
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000837:Anion Exchange Resins / Q000494:pharmacology; D019540:Area Under Curve; D001646:Bile / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000172:deficiency / Q000378:metabolism*; D001693:Biological Transport, Active; D002792:Cholestyramine Resin / Q000494:pharmacology; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000837:Anion Exchange Resins; D001647:Bile Acids and Salts; D000644:Quaternary Ammonium Compounds; D002792:Cholestyramine Resin; C043902:tri-n-butylmethylammonium