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Research ArticleArticle

A New Physiologically Based, Segregated-Flow Model to Explain Route-Dependent Intestinal Metabolism

Diem Cong, Margaret Doherty and K. Sandy Pang
Drug Metabolism and Disposition February 2000, 28 (2) 224-235;
Diem Cong
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Margaret Doherty
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K. Sandy Pang
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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

  • 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

  • ↵1 Present address: Victoria College of Pharmacy, Monash University, Melbourne, Australia.

  • 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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Drug Metabolism and Disposition: 28 (2)
Drug Metabolism and Disposition
Vol. 28, Issue 2
1 Feb 2000
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Research ArticleArticle

A New Physiologically Based, Segregated-Flow Model to Explain Route-Dependent Intestinal Metabolism

Diem Cong, Margaret Doherty and K. Sandy Pang
Drug Metabolism and Disposition February 1, 2000, 28 (2) 224-235;

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Research ArticleArticle

A New Physiologically Based, Segregated-Flow Model to Explain Route-Dependent Intestinal Metabolism

Diem Cong, Margaret Doherty and K. Sandy Pang
Drug Metabolism and Disposition February 1, 2000, 28 (2) 224-235;
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