Unequivocal Evidence Supporting the Segregated Flow Intestinal Model that Discriminates Intestine versus Liver First ‐Pass Removal in PBPK Modeling

Abstract Merits of the segregated flow model (SFM), highlighting the intestine as an inert serosa and active enterocyte c regions, with a smaller fractional (fQ < 0.3) intestinal flow (QI) perfusing the enterocyte region, were described. Less drug in the circulation reaches the enterocytes due to the lower flow (fQQI) in comparison to drug absorbed from the gut lumen, fostering the idea of route‐dependent intestinal removal. The SFM was superior over the traditional model (TM), which views the serosa and enterocytes as a well‐mixed tissue perfused by 100% QI. The SFM model was able to explain the lower extents of intestinal metabolism of enalapril, morphine, and midazolam with IV vs. PO dosing. For morphine, the urine/bile ratio of the metabolite, morphine glucuronide for PO was 2.6x that of IV. This was due the higher proportion of intestinally formed MG, appearing more in urine than bile due to low permeability and greater extent of intestinal formation with PO administration. By contrast, the TM predicted the same for PO vs. IV. The TM predicted that the intestine:liver contributions to first‐pass removal were 46%:53% for both PO and IV, whereas the SFM predicted 46%:53% for PO, but 9%:91% for IV. By contrast, the kinetics of codeine, precursor of morphine, was described equally well by the SFM‐ and TM‐PBPK models, suggesting that intestinal metabolism of codeine is negligible. Fits to these PBPK models further provided insightful information towards me...
Source: Biopharmaceutics and Drug Disposition - Category: Drugs & Pharmacology Authors: Tags: Special Issue Article Source Type: research