Abstract
Objectives
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.
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Abbreviations
- APC:
-
apparent partition coefficients
- CsA:
-
cyclosporine A
- MPP+ :
-
methyl-4-phenylpyridinium acetate
- Mw:
-
molecular weight
- OCT1:
-
organic cation transporter 1
- P-gp:
-
P-glycoprotein
- QACs:
-
Quaternary Ammonium Compounds
- TBA:
-
tetrabutyl ammonium
- TBuMA:
-
tributylmethyl ammonium
- TDC:
-
taurodeoxy cholate
- TEA:
-
tetraethyl ammonium
- TEER:
-
transepithelial electrical resistance
- TMA:
-
tetramethyl ammonium
- TPeA:
-
tetrapentyl ammonium
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Acknowledgments
This work was supported by a grant (No. CBM33-B4000-01-01-00) from the Center for Biological Modulators of the 21st Century Frontier R&D Program, Ministry of Science and Technology, Korea, and the Korea Health 21 R&D Project, Ministry of Health and Welfare (A030001), and by a grant from the Korean Ministry of Science and Technology through the National Research Laboratory Program (ROA-2006-000-10290-0).
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Im-Sook Song and Min-Koo Choi contributed equally to this work.
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Song, IS., Choi, MK., Jin, QR. et al. 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. Pharm Res 27, 823–831 (2010). https://doi.org/10.1007/s11095-010-0075-0
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DOI: https://doi.org/10.1007/s11095-010-0075-0