The Segregated Intestinal Flow Model (SFM) for Drug Absorption and Drug Metabolism: Implications on Intestinal and Liver Metabolism and Drug–Drug Interactions
The properties of the segregated flow model (SFM), which considers split intestinal flow patterns perfusing an active enterocyte region that houses enzymes and transporters (<20% of the total intestinal blood flow) and an inactive serosal region (>80%), were compared to those of the traditiona...
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MDPI AG
2020-04-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/12/4/312 |
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| author | K. Sandy Pang H. Benson Peng Keumhan Noh |
| author_facet | K. Sandy Pang H. Benson Peng Keumhan Noh |
| author_sort | K. Sandy Pang |
| collection | DOAJ |
| description | The properties of the segregated flow model (SFM), which considers split intestinal flow patterns perfusing an active enterocyte region that houses enzymes and transporters (<20% of the total intestinal blood flow) and an inactive serosal region (>80%), were compared to those of the traditional model (TM), wherein 100% of the flow perfuses the non-segregated intestine tissue. The appropriateness of the SFM model is important in terms of drug absorption and intestinal and liver drug metabolism. Model behaviors were examined with respect to intestinally (M1) versus hepatically (M2) formed metabolites and the availabilities in the intestine (F<sub>I</sub>) and liver (F<sub>H</sub>) and the route of drug administration. 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. 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 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. A similar pattern exists for drug–drug interactions (DDIs). The inhibitor or inducer exerts its greatest effect on victim drugs when both inhibitor/inducer and drug are given po. With po dosing, more drug or inhibitor/inducer is brought into the intestine for DDIs. The bypass of flow and drug to the enterocyte region of the intestine after intravenous administration adds complications to in vitro–in vivo extrapolations (IVIVE). |
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| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T20:45:28Z |
| publishDate | 2020-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-f2951a68d3ea45c1b041c37fad74acf32023-11-19T20:24:00ZengMDPI AGPharmaceutics1999-49232020-04-0112431210.3390/pharmaceutics12040312The Segregated Intestinal Flow Model (SFM) for Drug Absorption and Drug Metabolism: Implications on Intestinal and Liver Metabolism and Drug–Drug InteractionsK. Sandy Pang0H. Benson Peng1Keumhan Noh2Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, CanadaLeslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, CanadaLeslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, CanadaThe properties of the segregated flow model (SFM), which considers split intestinal flow patterns perfusing an active enterocyte region that houses enzymes and transporters (<20% of the total intestinal blood flow) and an inactive serosal region (>80%), were compared to those of the traditional model (TM), wherein 100% of the flow perfuses the non-segregated intestine tissue. The appropriateness of the SFM model is important in terms of drug absorption and intestinal and liver drug metabolism. Model behaviors were examined with respect to intestinally (M1) versus hepatically (M2) formed metabolites and the availabilities in the intestine (F<sub>I</sub>) and liver (F<sub>H</sub>) and the route of drug administration. 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. 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 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. A similar pattern exists for drug–drug interactions (DDIs). The inhibitor or inducer exerts its greatest effect on victim drugs when both inhibitor/inducer and drug are given po. With po dosing, more drug or inhibitor/inducer is brought into the intestine for DDIs. The bypass of flow and drug to the enterocyte region of the intestine after intravenous administration adds complications to in vitro–in vivo extrapolations (IVIVE).https://www.mdpi.com/1999-4923/12/4/312segregated flow intestinal model (SFM)traditional model (TM)route-dependent intestinal metabolismfirst-pass effectdrug-drug interactionsDDI |
| spellingShingle | K. Sandy Pang H. Benson Peng Keumhan Noh The Segregated Intestinal Flow Model (SFM) for Drug Absorption and Drug Metabolism: Implications on Intestinal and Liver Metabolism and Drug–Drug Interactions Pharmaceutics segregated flow intestinal model (SFM) traditional model (TM) route-dependent intestinal metabolism first-pass effect drug-drug interactions DDI |
| title | The Segregated Intestinal Flow Model (SFM) for Drug Absorption and Drug Metabolism: Implications on Intestinal and Liver Metabolism and Drug–Drug Interactions |
| title_full | The Segregated Intestinal Flow Model (SFM) for Drug Absorption and Drug Metabolism: Implications on Intestinal and Liver Metabolism and Drug–Drug Interactions |
| title_fullStr | The Segregated Intestinal Flow Model (SFM) for Drug Absorption and Drug Metabolism: Implications on Intestinal and Liver Metabolism and Drug–Drug Interactions |
| title_full_unstemmed | The Segregated Intestinal Flow Model (SFM) for Drug Absorption and Drug Metabolism: Implications on Intestinal and Liver Metabolism and Drug–Drug Interactions |
| title_short | The Segregated Intestinal Flow Model (SFM) for Drug Absorption and Drug Metabolism: Implications on Intestinal and Liver Metabolism and Drug–Drug Interactions |
| title_sort | segregated intestinal flow model sfm for drug absorption and drug metabolism implications on intestinal and liver metabolism and drug drug interactions |
| topic | segregated flow intestinal model (SFM) traditional model (TM) route-dependent intestinal metabolism first-pass effect drug-drug interactions DDI |
| url | https://www.mdpi.com/1999-4923/12/4/312 |
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