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.
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.
Song
Im-Sook
IS
Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Busan, 614-735, Korea.
Choi
Min-Koo
MK
Jin
Qing-Ri
QR
Shim
Won-Sik
WS
Shim
Chang-Koo
CK
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
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