title: Increased affinity to canalicular P-gp via formation of lipophilic ion-pair complexes with endogenous bile salts is associated with mw threshold in hepatobiliary excretion of quaternary ammonium compounds.
abstract: OBJECTIVE
  We intended to elucidate the mechanism of the molecular weight (Mw) threshold (i.e., 200 +/- 50) for appreciable hepatobiliary excretion of quaternary ammonium compounds (QACs) in rats.
  
  
  METHODS
  We measured the effect of ion-pair complexation of QACs with taurodeoxycholate (TDC), an endogenous anionic bile salt, on the apparent partition coefficients (APC) of QACs between n-octanol and phosphate buffer, and the inhibition of organic cation transporter1 (OCT1)- and P-glycoprotein (P-gp)-mediated transport of representative substrates.
  
  
  RESULTS
  By measuring the APC, we demonstrated that there is a Mw threshold of 200 +/- 50 in the ion-pair complexation of QACs with an endogenous bile salt, TDC. We also demonstrated, by measuring the inhibition of relevant transports, that a Mw threshold of 200 +/- 50 exists for the binding of QACs to canalicular P-gp, but not for sinusoidal OCT1. The Mw threshold values for ion-pair formation and P-gp binding were identical and consistent with the reported Mw threshold value for appreciable biliary excretion of QACs in rats.
  
  
  CONCLUSIONS
  Mw-dependent binding of QACs to canalicular P-gp contributes in part to the mechanism of the Mw threshold of 200 +/- 50. The formation of lipophilic ion-pair complexes with bile salts, followed by stronger binding to canalicular P-gp, appears to accelerate biliary excretion of QACs with a high Mw.
authors.affiliation: Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Busan, 614-735, Korea.
authors.forename: Im-Sook
authors.initials: IS
authors.lastname: Song
authors.forename: Min-Koo
authors.initials: MK
authors.lastname: Choi
authors.forename: Qing-Ri
authors.initials: QR
authors.lastname: Jin
authors.forename: Won-Sik
authors.initials: WS
authors.lastname: Shim
authors.forename: Chang-Koo
authors.initials: CK
authors.lastname: Shim
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001646:Bile / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000378:metabolism*; D001648:Bile Canaliculi / Q000378:metabolism*; D001693:Biological Transport, Active; D015153:Blotting, Western; D050482:Catecholamine Plasma Membrane Transport Proteins / Q000378:metabolism; D002460:Cell Line; D003627:Data Interpretation, Statistical; D003630:Daunorubicin / Q000378:metabolism; D004285:Dogs; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000378:metabolism*; D008970:Molecular Weight; D000644:Quaternary Ammonium Compounds / Q000378:metabolism*; D051381:Rats; D012995:Solubility; D013657:Taurodeoxycholic Acid / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001647:Bile Acids and Salts; D050482:Catecholamine Plasma Membrane Transport Proteins; D008055:Lipids; D000644:Quaternary Ammonium Compounds; C493212:Slc22a1 protein, rat; D013657:Taurodeoxycholic Acid; D015655:1-Methyl-4-phenylpyridinium; D003630:Daunorubicin