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Mol Pharm. 2013 Nov 4;10(11):3989-96. doi: 10.1021/mp400179v. Epub 2013 Jul 12.

Ion pairing with bile salts modulates intestinal permeability and contributes to food-drug interaction of BCS class III compound trospium chloride.

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Department of Pharmaceutical Technology & Biopharmaceutics, Johannes Gutenberg University , Staudingerweg 5, 55128 Mainz, Germany.


In the current study the involvement of ion pair formation between bile salts and trospium chloride (TC), a positively charged Biopharmaceutical Classification System (BCS) class III substance, showing a decrease in bioavailability upon coadministration with food (negative food effect) was investigated. Isothermal titration calorimetry provided evidence of a reaction between TC and bile acids. An effect of ion pair formation on the apparent partition coefficient (APC) was examined using (3)H-trospium. The addition of bovine bile and bile extract porcine led to a significant increase of the APC. In vitro permeability studies of trospium were performed across Caco-2-monolayers and excised segments of rat jejunum in a modified Ussing chamber. The addition of bile acids led to an increase of trospium permeation across Caco-2-monolayers and rat excised segments by approximately a factor of 1.5. The addition of glycochenodeoxycholate (GCDC) was less effective than taurodeoxycholate (TDOC). In the presence of an olive oil emulsion, a complete extinction of the permeation increasing effects of bile salts was observed. Thus, although there are more bile acids in the intestine in the fed state compared to the fasted state, these are not able to form ion pairs with trospium in fed state, because they are involved in the emulsification of dietary fats. In conclusion, the formation of ion pairs between trospium and bile acids can partially explain its negative food effect. Our results are presumably transferable to other organic cations showing a negative food effect.

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