Unequivocal evidence supporting the segregated flow intestinal model that discriminates intestine versus liver first‐pass removal with PBPK modeling

Abstract

Merits of the segregated flow model (SFM), highlighting the intestine as inert serosa and active enterocyte regions, with a smaller fractional (f < 0.3) intestinal flow (Q ) perfusing the enterocyte region, are described. Less drug in the circulation reaches the enterocytes due to the lower flow (f Q ) in comparison with drug administered into the gut lumen, fostering the idea of route-dependent intestinal removal. The SFM has been found superior to the traditional model (TM), which views the serosa and enterocytes totally as a well-mixed tissue perfused by 100% of the intestinal flow, Q . The SFM model is able to explain the lower extents of intestinal metabolism of enalapril, morphine and midazolam with i.v. vs. p.o. dosing. For morphine, the urine/bile ratio of the metabolite, morphine glucuronide MGurineMGbile for p.o. was 2.6× that of i.v. This was due to the higher proportion of intestinally formed morphine glucuronide, appearing more in urine than in bile due to its low permeability and greater extent of intestinal formation with p.o. administration. By contrast, the TM predicted the same MGurineMGbile for p.o. vs. i.v. The TM predicted that the contributions of the intestine:liver to first-pass removal were 46%:54% for both p.o. and i.v. The SFM predicted same 46%:54% (intestine:liver) for p.o., but 9%:91% for i.v. By contrast, the kinetics of codeine, the precursor of morphine, was described equally well by the SFM- and TM-PBPK models, a trend suggesting that intestinal metabolism of codeine is negligible. Fits to these PBPK models further provide insightful information towards metabolite formation: available fractions and the fractions of hepatic and total clearances that form the metabolite in question. The SFM-PBPK model is useful to identify not only the presence of intestinal metabolism but the contributions of the intestine and liver for metabolite formation. Copyright © 2016 John Wiley & Sons, Ltd.

Revisiting the role of gut wall in the fate of orally administered drugs: Why now and to what effect?

“…Readers who are interested in the application of models should consider another aspect that had surfaced with the development of the SFM. This is regarding the phenomenon of route‐independent intestinal metabolism, namely, a disproportionately higher extent of intestinal metabolism occurs with oral dosing, a condition contrasting the virtual absence or much lower intestinal metabolism with intravenous dosing . Cong et al developed the SFM that described the intestinal flow as being segregated in perfusing the enterocyte region of high metabolic and absorptive activities (5–30% intestinal flow, denoted by the fractional flow, f Q Q I ), and a flow to the non‐active serosal region as (1 − f Q ) Q I .…”

“…The second Theme issue deals more with strategies for the prediction of in vivo observations from non‐clinical data on an industrial scale by Yau et al , the provision of scaling factors for gut‐wall enzymes by Hatley et al , the critical assessment of predicting pediatric drug absorption by applying physiologically based pharmacokinetics (PBPK) modelling by Nicolas et al , and the ability to predict inhibitory effects on intestinal metabolism by employing PBPK models that account for variations of metabolism in different (enterocyte vs. serosal) regions of the gut (Pang et al . ). The themes issue concludes with two further applications of relatively more complex models that explore intestinal metabolism, transport and associated interactions by Johnson et al and Liu et al .…”

“…Many of the experimental data that show route‐dependent nature of intestinal drug metabolism has been summarized in the theme 2 issue by Pang et al . . The Q Gut model, developed by Yang et al .…”

“…The route‐dependent intestinal metabolism of morphine is apparent oral vs. intravenous morphine administration, that and a disproportionately greater extent of metabolism occurs by the intestine for oral dosing (for details, see Yang et al , ). In stark contrast, data fitting obtained from rat in vivo metabolism of codeine, precursor to morphine, with the TM and SFM revealed that there was no discrepancy between the models, suggesting a lack of intestinal metabolism .…”

A permeability‐ and perfusion‐based PBPK model for improved prediction of concentration‐time profiles

“…C1 includes muscle, skin and ¼ rest‐of‐body (RB), C2 includes bone and ¼ RB, C3 includes heart and ¼ RB, and C4 includes kidney and ¼ RB. The gut was segregated into mesentery/gut serosa and mucosa (Segregated Flow Model) as described by Pang 21 , 22 This is particularly important when considering gut clearance. Also, capillaries of the gut mucosa are fenestrated whereas other capillaries of the gut are not.…”