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Article CommentaryCommentary

Commentary: Theoretical Predictions of Flow Effects on Intestinal and Systemic Availability in Physiologically Based Pharmacokinetic Intestine Models: The Traditional Model, Segregated Flow Model, and QGut Model

K. Sandy Pang and Edwin C. Y. Chow
Drug Metabolism and Disposition October 2012, 40 (10) 1869-1877; DOI: https://doi.org/10.1124/dmd.112.045872
K. Sandy Pang
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
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Edwin C. Y. Chow
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
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Abstract

Physiologically based pharmacokinetic (PBPK) models for the intestine, comprising of different flow rates perfusing the enterocyte region, were revisited for appraisal of flow affects on the intestinal availability (FI) and, in turn, the systemic availability (Fsys) and intestinal versus liver contribution to the first-pass effect during oral drug absorption. The traditional model (TM), segregated flow model (SFM), and effective flow (QGut) model stipulate that 1.0, ∼0.05 to 0.3, and ≤0.484× of the total intestinal flow, respectively, reach the enterocyte region that houses metabolically active and transporter-enriched enterocytes. The fractional flow rate to the enterocyte region (fQ), when examined under varying experimental conditions, was found to range from 0.024 to 0.2 for the SFM and 0.065 to 0.43 for the QGut model. Appraisal of these flow intestinal models, when used in combination with whole-body PBPK models, showed the ranking as SFM < QGut model < TM in the description of FI, and the same ranking existed for the contribution of the intestine to first-pass removal. However, the ranking for the predicted contribution of hepatic metabolism, when present, to first-pass removal was the opposite: SFM > QGut model > TM. The findings suggest that the fQ value strongly influences the rate of intestinal metabolism (FI and Fsys) and indirectly affects the rate of liver metabolism due to substrate sparing effect. Thus, the fQ value in the intestinal flow models pose serious implications on the interpretation of data on the first-pass effect and oral absorption of drugs.

Footnotes

  • This work was supported by the Canadian Institute for Health Research (to K.S.P.); and the Alexander Graham Bell National Science and Engineering Research Council (NSERC) fellowship, National Science and Engineering Research Council of Canada, NSERC (to E.C.Y.C.).

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    http://dx.doi.org/10.1124/dmd.112.045872.

  • ABBREVIATIONS:

    PBPK
    physiologically based pharmacokinetic
    FI or FG
    intestinal availability
    FH
    hepatic availability
    Fsys
    systemic availability
    Fabs
    fraction absorbed
    TM
    traditional model
    SFM
    segregated flow model
    Qen
    low enterocyte flow
    fQ
    fractional flow rate to the enterocyte region
    QPV
    portal venous flow
    Qgut
    effective flow
    Qvilli
    villous flow
    P-gp
    P-glycoprotein
    po
    oral
    iv
    intravenous
    CLint,met
    metabolic intrinsic clearance
    P
    precursor drug
    CLint,met1,H
    metabolic intrinsic clearance for liver
    CLint,sec,I
    intestinal secretion clearance
    CLint,sec,H
    liver biliary intrinsic clearance
    CLd1 and CLd2
    influx and efflux intrinsic clearances
    CLint,I
    total intestinal intrinsic clearance
    CLint,H
    total liver intrinsic clearance
    fB
    unbound fraction in blood
    fI
    unbound fraction in intestine
    fH
    unbound fraction in liver
    AUC
    area under the curve
    ka
    absorption rate constant
    kg
    luminal degradation rate constant
    Papp
    apparent permeability
    CLperm
    drug permeability clearance
    Peff
    effective permeability
    vI
    rate of intestinal removal
    vH
    rate of hepatic removal
    E
    extraction ratio
    CA
    arterial concentration
    STM
    segmental traditional model
    SSFM
    segmental segregated flow model
    C̅PV
    flow-averaged portal venous concentration.

  • Received March 30, 2012.
  • Accepted June 27, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (10)
Drug Metabolism and Disposition
Vol. 40, Issue 10
1 Oct 2012
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Article CommentaryCommentary

INTESTINAL FLOW MODELS IN PBPK MODELING

K. Sandy Pang and Edwin C. Y. Chow
Drug Metabolism and Disposition October 1, 2012, 40 (10) 1869-1877; DOI: https://doi.org/10.1124/dmd.112.045872

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Article CommentaryCommentary

INTESTINAL FLOW MODELS IN PBPK MODELING

K. Sandy Pang and Edwin C. Y. Chow
Drug Metabolism and Disposition October 1, 2012, 40 (10) 1869-1877; DOI: https://doi.org/10.1124/dmd.112.045872
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