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• W2600355553 abstract "Metabolites arising from new chemical entities are mediators of toxicity. Frequently, metabolites are required for testing in animals or humans, when these are found toxic or active, with the expectation that the exposure effects mimic those of their former counterparts. Therefore, there is a need to understand the kinetics of metabolite formation. This article highlights the intestine and liver as first-pass drug metabolizing tissues. Physiologically based pharmacokinetic models, including the segregated flow model (SFM) for the intestine, with partial and low flow perfusion the enterocyte region, is compared and contrasted with its counterpart, the traditional model (TM), for which the entire blood flow perfuses the intestinal tissue as a whole. The impact of the SFM translates to route-dependent intestinal metabolism, namely, there will be a greater extent of intestinal drug metabolism for orally versus intravenously administered drug. In contrast, the TM predicts identical extents for both. A higher extent of intestinal morphine glucuronidation is implicated in rat in vivo with oral dosing (46% vs. only 9% contribution from intestine to first-pass metabolism for oral b intravenous dosing). Data on the TM versus SFM could reveal absence of intestinal metabolism. Equally well-fitted results obtained with SFM and TM, as shown for the metabolism of codeine in the rat, reveal the absence of intestinal metabolism. Inclusion of heterogeneity in enzymes/transporters in the intestine and liver will bring about refinement in the description of metabolite kinetics." @default.
• W2600355553 created "2017-04-07" @default.
• W2600355553 creator A5020086601 @default.
• W2600355553 creator A5053305926 @default.
• W2600355553 date "2017-01-01" @default.
• W2600355553 modified "2023-09-24" @default.
• W2600355553 title "PBPK Modeling to Estimate Metabolite Formation From First-Pass Organs: Intestine and Liver" @default.
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