Theoretical consideration of the properties of intestinal flow models on route-dependent drug removal: Segregated Flow (SFM) vs. Traditional (TM)

The intestine is endowed with a plethora of enzymes and transporters and regulates the flow of substrate to the liver. Physiologically-based pharmacokinetic models have surfaced to describe intestinal removal. The traditional model (TM) describes the intestinal flow as a whole perfusing the entire tissue that contains the intestinal transporters and enzymes. The segregated flow model (SFM) describes that only a fraction (f(Q) < 0.2) of the intestinal blood flow perfuses the enterocyte region where the intestinal enzymes and transporters are housed, rendering a lower drug distribution/intestinal clearance when drug enters via the circulation than from the gut lumen. As shown by simulations, a higher intestinal clearance and extraction ratio (E-I,E-iv) exists for the TM than for SFM after iv dosing. By contrast, the E-I,E-po after po dosing is higher for the SFM, due to the smaller volume of distribution for the enterocyte region and a lower flow rate that result in increased mean residence time and higher drug extraction. Under MBI (mechanism-based inhibition), the AUC(R,po) after oral bolus is the highest for drug when inhibitor is given orally, with SFM > TM. Competitive inhibition of intestinal enzymes leads to higher liver metabolism; again, when both drug and inhibitor are given orally, changes in the SFM > TM. However, less definitive patterns result with inhibition of both intestinal and liver enzymes. In conclusion, differences exist for E-I and drug-drug interaction (DDI) between the TM and SFM. The fractional intestinal blood flow (f(Q)) is a key factor affecting different extents of intestinal/liver metabolism of the drug after oral as well as intravenous administration.