With po dosing, more drug or inhibitor/inducer is brought into the intestine for DDIs. The inhibitor or inducer exerts its greatest effect on victim drugs when both inhibitor/inducer and drug are given po. A similar pattern exists for drug–drug interactions (DDIs). The SFM is significant, as this drug metabolism model explains route-dependent intestinal metabolism, describing a higher extent of intestinal metabolism with po versus the much reduced or absence of intestinal metabolism with iv dosing. The SFM predicts the highest and lowest M1 formed with oral (po) and intravenous (iv) dosing, respectively, whereas the extent of M1 formation is similar for the drug administered po or iv according to the TM, and these values sit intermediate those of the SFM. The %contribution of the intestine to total first-pass metabolism bears a reciprocal relation to that for the liver, since the intestine, a gateway tissue, regulates the flow of substrate to the liver. Model behaviors were examined with respect to intestinally (M1) versus hepatically (M2) formed metabolites and the availabilities in the intestine (FI) and liver (FH) and the route of drug administration. The appropriateness of the SFM model is important in terms of drug absorption and intestinal and liver drug metabolism. The properties of the segregated flow model (SFM), which considers split intestinal flow patterns perfusing an active enterocyte region that houses enzymes and transporters (80%), were compared to those of the traditional model (TM), wherein 100% of the flow perfuses the non-segregated intestine tissue.
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