Abstract
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 (FI) and liver (FH) 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).
Highlights
The extent of the absorption of orally administered drugs is controlled by the intestine and liver, which are anatomically linked as a serial unit that is sequentially perfused by the circulation (Figure 1)
This review has highlighted that metabolite formation and drug–drug interactions (DDIs) of the intestine are not well predicted by the traditional intestinal flow model (TM) with respect to the routes of administration of drug and inhibitor
We recognize the importance of the segregated flow model (SFM) as the premier model to examine intestinal drug metabolism
Summary
The extent of the absorption of orally administered drugs is controlled by the intestine and liver, which are anatomically linked as a serial unit that is sequentially perfused by the circulation (Figure 1). TSoeiglemuemnt[-2d7e]paennddpenHt dcheacnlignees in meamlobnrgantehpe eirnmteesatbinileity[8, ,r2e8d]uacreed nsuortefadc.eTahreeasefrvoamriathbeledsuwodilel nmuomdutolaitleeutmhe[2e7x]teanntdopfHpcahssainvgeesdraulogng theaibnstoersptitnioen[.8,28] are noted These variables will modulate the extent of passive drug absorption. BBeeccaauusseeooffinintetestsitninalarlermemovoavla[le[xetxratrcaticotniornatriaot,io, EI oErI o(r1 (−1 F−IF)]I),]t,htheeddruruggeennteterriinnggtthhee lliivveerr iiss rreedduucceedd,, aannddtthheelliviveerrmmaayyfufurtrhthererrermemovoevtehtehderdurguwg iwthith a liavelirveerxetrxatcraticotinonrartaiotio(E(EHH))ttoo eeffffeecctt ffiirrsstt--ppaassssmmeetatabboolilsimsm. Following oral (po) drug dosing, the fraction of the dose absorbed (Fa) is attributed to dosage forms and/or solubility properties, intestinal removal via metabolism or secretion (defined by the intestinal extraction ratio, EI), and liver removal (defined as the hepatic extraction ratio, EH), respectively. The product of the availabilities, FaFIFH, constitute the net fraction, the systemic availability, Fsys For this reason, the intestine and liver are both capable of removing a significant proportion of the orally administered dose, a phenomenon known as the first-pass effect [46]. The extent of intestinal versus liver removal of drugs is intimately related [47,48,49,50]
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