Metabolism of XXXX via enteric recycling: role of intestinal disposition.

@entity670 @entity3088 @entity15476 @entity8686 @entity35 @entity597
The purpose of this study was to determine the importance of intestinal disposition in the first-pass metabolism of @entity3088 . A four-site perfused @entity35 intestinal model, @entity35 liver and intestinal microsomes, Caco-2 cell microsomes, and the Caco-2 cell culture model were used. In the four-site model, approximately 28% of perfused aglycones are absorbed (approximately 450 nmol/30 min). Both absorption and subsequent excretion of metabolites were rapid and site-dependent (p < 0.05). Maximal amounts of intestinal conjugates excreted per 30 min were 61 and 150 nmol for @entity670 and @entity15476 , respectively. Maximal amounts of biliary conjugates excreted per 30 min were 50 and 30 nmol for @entity670 and @entity15476 , respectively. Microsomes, prepared from Caco-2 cells, @entity35 intestine, and @entity35 liver, always glucuronidated @entity15476 faster than @entity670 (p < 0.05). In addition, @entity35 jejunal microsomes glucuronidated both @entity3088 faster (p < 0.05) than @entity35 intestinal microsomes prepared from other regions. When comparing glucuronidation in different organs, jejunal microsomes often but not always glucuronidated both @entity3088 faster than liver microsomes. In the Caco-2 model, both @entity3088 were rapidly absorbed and rapidly conjugated, and the conjugates were excreted apically and basolaterally. Similar to the four-site perfusion model, @entity15476 conjugates were excreted much faster than @entity670 conjugates (>2.5 times for @entity8686 , >4.5 times for @entity597 ; p < 0.05). In conclusion, intestinal disposition may be more important than hepatic disposition in the first-pass metabolism of @entity3088 such as @entity15476 . In conjunction with enterohepatic recycling, enteric recycling may be used to explain why @entity3088 have poor systemic bioavailabilities.
