Abstract
Processes of intestinal absorption, metabolism, and secretion must be considered simultaneously in viewing oral drug bioavailability. Existing models often fail to predict route-dependent intestinal metabolism, namely, little metabolism occurs after systemic dosing but notable metabolism exists after oral dosing. A physiologically based,Segregated-Flow Model (SFM) was developed to examine the influence of intestinal transport (absorption and exsorption), metabolism, flow, tissue-partitioning characteristics, and elimination in other organs on intestinal clearance, intestinal availability, and systemic bioavailability. For the SFM, blood flow to intestine was effectively segregated for the perfusion of two regions, with 10% reaching an absorptive layer–the enterocytes at the villus tips of the mucosa where metabolic enzymes and the P-glycoprotein reside, and the remaining 90% supplying the rest of the intestine (serosa and submucosa), a nonabsorptive layer. The traditional, physiologically-based model, which regards the intestine as a single, homogeneous compartment with all of the intestinal blood flow perfusing the tissue, was also examined for comparison. The analytical solutions under first order conditions were essentially identical for the SFM and traditional model, differing only in the flow rate to the absorptive/removal region. The presence of other elimination organs did not affect the intestinal clearance and bioavailability estimates, but reduced the percentage of dose metabolized by the intestine. For both models, intestinal availability was inversely related to the intrinsic clearances for intestinal metabolism and exsorption, and was additionally affected by both the rate constant for absorption and that denoting luminal loss when drug was exsorbed. However, the effect of secretion by P-glycoprotein became attenuated with rapid absorption. The difference in flow between models imparted a substantial influence on the intestinal clearance of flow-limited substrates, and the SFM predicted markedly higher extents of intestinal metabolism for oral over i.v. dosing. Thus, the SFM provides a physiological view of the intestine and explains the observation of route-dependent, intestinal metabolism.
Footnotes
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Send reprint requests to: Dr. K. S. Pang, Faculty of Pharmacy, University of Toronto, 19 Russell Toronto, Ontario, Canada M5S 2S2. E-mail: pang{at}phm.utoronto.ca
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↵1 Present address: Victoria College of Pharmacy, Monash University, Melbourne, Australia.
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This work was supported by the Medical Research Council of Canada (MA9104 and MOP36,457); D.C. was a recipient of the Ontario Graduate Scholarship, Canada.
- Abbreviations:
- Pgp
- P-glycoprotein
- AUC
- area under the concentration-time curve
- CLd1
- influx intrinsic clearance from blood compartment to enterocyte compartment
- CLd2
- efflux intrinsic clearance from enterocyte compartment to blood compartment
- CLd3
- influx intrinsic clearance from blood compartment to serosal compartment
- CLd4
- efflux intrinsic clearance from serosal compartment to blood compartment
- CLI
- intestinal clearance
- CLothers
- clearance by other parallel organs
- CLm
- metabolic intrinsic clearance of intestine
- CLsec
- secretory intrinsic clearance of intestine
- CLt
- total body or systemic clearance
- Fabs
- fraction absorbed
- FI
- intestinal availability
- Fsys
- systemic bioavailability
- ka
- absorption rate constant
- kg
- luminal degradation constant
- Qen
- flow to the enterocyte layer of the mucosa
- QI
- total flow to the intestine
- SFM
- segregated-flow model
- TM
- traditional model
- M
- morphine
- M3G
- morphine-3β-glucuronide
- Received May 24, 1999.
- Accepted October 1, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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