Disposition of Formononetin via Enteric Recycling: Metabolism and Excretion in Mouse Intestinal Perfusion and Caco-2 Cell Models

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Abstract
The purpose of this study was to determine the absorption and metabolism of formononetin using the mouse intestinal perfusion model, mouse intestinal homogenate, and the Caco-2 cell culture model. In the perfusion model where upper and lower small intestine were perfused simultaneously, absorption of formononetin was rapid and dimensionless effective permeabilities of formononetin (2.53−2.90) were similar to those for rats. Moreover, the amounts of sulfates excreted in mouse intestine (8−11 nmol/30 min/10 cm) were significantly higher than those for rats whereas the amounts of glucuronides excreted (7−10 nmol/30 min/10 cm) were comparable. Small amounts of formononetin glucuronide but not sulfate were found in mouse bile, but the total amounts were 120 times less than those for rats. Multidrug-resistance-related protein (MRP) inhibitors (leukotriene C4 plus MK-571, C26H26ClN2O3S2) significantly decreased the excretion of glucuronide and sulfate in mouse intestine (52−74% for glucuronide, 13−26% for sulfate) and in Caco-2 cells (92% for glucuronide, 37% for sulfate). They also inhibited formation of conjugates in intestinal homogenate (∼60% for glucuronide, ∼30% for sulfate) and Caco-2 cell lysate (∼92% for glucuronide, ∼37% for sulfate). Organic anion transporter (OAT) inhibitors (estrone sulfate plus dihydroepiandrosterone sulfate) did not significantly change the excretion of formononetin conjugates in either model, even though they significantly decreased the formation of both. In conclusion, our study showed that formononetin has similar absorption in rat and mouse intestine, but metabolism was species-dependent. The mouse perfusion model may have an advantage over the rat intestinal perfusion model for flavonoid disposition studies in that both sulfates and glucuronides are excreted, as shown in humans. Keywords: Conjugates; coupling; excretion; mouse intestine; perfusion; formononetin

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