Triple Recycling Processes Impact Systemic and Local Bioavailability of Orally Administered Flavonoids

Abstract

Abstract. Triple recycling (i.e., enterohepatic, enteric and local recycling) plays a central role in governing the disposition of phenolics such as flavonoids, resulting in low systemic bioavailability but higher gut bioavailability and longer than expected apparent half-life. The present study aims to investigate the coexistence of these recycling schemes using model bioactive flavonoid tilianin and a foursite perfused rat intestinal model in the presence or absence of a lactase phlorizin hydrolase (LPH) inhibitor gluconolactone and/or a glucuronidase inhibitor saccharolactone. The result showed that tilianin could be metabolized into tilianin glucuronide, acacetin, and acacetin glucuronide, which are excreted into the bile and luminal perfusate (highest in the duodenum and lowest in the colon). Gluconolactone (20 mM) significantly reduced the absorption of tilianin and the enteric and biliary excretion of acacetin glucuronide. Saccharolactone (0.1 mM) alone or in combination of gluconolactone also remarkably reduced the biliary and intestinal excretion of acacetin glucuronide. Acacetin glucuronides from bile or perfusate were rapidly hydrolyzed by bacterial β-glucuronidases to acacetin, enabling enterohepatic and enteric recycling. Moreover, saccharolactone-sensitive tilianin disposition and glucuronide deconjugation, which was more active in the small intestine than the colon, points to the small intestinal origin of the deconjugation enzyme and supports the presence of local recycling scheme. In conclusion, our studies have demonstrated triple recycling of a bioactive phenolic (i.e., a model flavonoid), and this recycling may have an impact on the site and duration of polyphenols pharmacokinetics in vivo.

SGLT-1 Transport and Deglycosylation inside Intestinal Cells Are Key Steps in the Absorption and Disposition of Calycosin-7-O- -D-Glucoside in Rats

“…This result differed from previous reports, which showed that hydrolysis by LPH was a critical first step in the disposition of isoflavonoid glucosides. We used the rat intestinal perfusion model, which has been demonstrated to be suitable for studying the role of LPH (Dai et al, 2015), and found that LPH inhibitor played minimal role in CG absorption and metabolism in the intestine (Fig. 3,D-F ;Fig.…”

Glyceollin Effects on MRP2 and BCRP in Caco-2 Cells, and Implications for Metabolic and Transport Interactions

“…Associated with this effort, pharmacokinetic studies have revealed poor bioavailability of these phytochemicals due to extensive metabolism (3). As an example, systematic investigations of genistein intestinal and hepatic disposition have revealed an elaborate integration of intestinal metabolism, and subsequent carrier-mediated apically-directed efflux of metabolites that severely limit genistein systemic bioavailability following oral ingestion (4). …”

Intestinal disposition of quercetin and its phase-II metabolites after oral administration in healthy volunteers

“…Clinical studies involving quercetin and ileostomists have also been conducted . Several research groups have used mice and rats to study the intestinal metabolism and efflux of other flavonoids . Recycling mechanisms (local, enteric and enterohepatic recycling) have been highlighted for flavonoid metabolites.…”