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Research ArticleArticle

Prediction of Human Intestinal First-Pass Metabolism of 25 CYP3A Substrates from In Vitro Clearance and Permeability Data

Michael Gertz, Anthony Harrison, J. Brian Houston and Aleksandra Galetin
Drug Metabolism and Disposition July 2010, 38 (7) 1147-1158; DOI: https://doi.org/10.1124/dmd.110.032649
Michael Gertz
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Anthony Harrison
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J. Brian Houston
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Aleksandra Galetin
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Abstract

Intestinal first-pass metabolism may contribute to low oral drug bioavailability and drug-drug interactions, particularly for CYP3A substrates. The current analysis predicted intestinal availability (FG) from in vitro metabolic clearance and permeability data of 25 drugs using the QGut model. The drug selection included a wide range of physicochemical properties and in vivo FG values (0.07–0.94). In vitro clearance data (CLuint) were determined in human intestinal (HIM) and three liver (HLM) microsomal pools (n = 105 donors) using the substrate depletion method. Apparent drug permeability (Papp) was determined in Caco-2 and Madin-Darby canine kidney cells transfected with human MDR1 gene (MDCK-MDR1 cells) under isotonic conditions (pH = 7.4). In addition, effective permeability (Peff) data, estimated from regression analyses to Papp or physicochemical properties were used in the FG predictions. Determined CLuint values ranged from 0.022 to 76.7 μl/min/pmol of CYP3A (zolpidem and nisoldipine, respectively). Differences in CLuint values obtained in HIM and HLM were not significant after normalization for tissue-specific CYP3A abundance, supporting their interchangeable usability. The FG predictions were most successful when Papp data from Caco-2/MDCK-MDR1 cells were used directly; in contrast, the use of physicochemical parameters resulted in significant FG underpredictions. Good agreement between predicted and in vivo FG was noted for drugs with low to medium intestinal extraction (e.g., midazolam predicted FG value 0.54 and in vivo value 0.51). In contrast, low prediction accuracy was observed for drugs with in vivo FG <0.5, resulting in considerable underprediction in some instances, as for saquinavir (predicted FG is 6% of the observed value). Implications of the findings are discussed.

Footnotes

  • M.G. was supported by a Ph.D. studentship from Pfizer Global Research and Development, Sandwich, Kent, UK.

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

    doi:10.1124/dmd.110.032649.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    FG
    intestinal availability
    QGut
    hybrid parameter of blood flow and drug permeability
    Papp
    apparent permeability
    A
    apical
    B
    basolateral
    MDCK-MDR1
    Madin-Darby canine kidney cells transfected with multidrug resistance 1
    Peff
    effective permeability
    CLint
    intrinsic clearance
    CLint,h
    hepatic intrinsic clearance
    CLint,g
    intestinal intrinsic clearance
    CLuint
    unbound intrinsic clearance
    Qent
    enterocytic blood flow
    fu
    fraction unbound
    HLM
    human liver microsomes
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry
    HIM
    human intestinal microsome(s)
    Rb
    blood/plasma distribution ratio
    AUC
    area under the curve
    Qh
    hepatic blood flow
    CLh
    hepatic blood clearance
    P-gp
    P-glycoprotein
    CP-100356
    N-(3,4-dimethoxyphenethyl)-4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2[1H]-yl)-6,7-dimethoxyquinazolin-2-amine
    MEM
    minimal essential medium
    HBSS
    Hanks' balanced salt solution
    ER
    efflux ratio
    gmfe
    geometric fold error
    rmse
    root mean square error
    UGT
    UDP glucuronosyltransferase.

  • Received February 8, 2010.
  • Accepted April 5, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (7)
Drug Metabolism and Disposition
Vol. 38, Issue 7
1 Jul 2010
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Research ArticleArticle

Prediction of Human Intestinal First-Pass Metabolism of 25 CYP3A Substrates from In Vitro Clearance and Permeability Data

Michael Gertz, Anthony Harrison, J. Brian Houston and Aleksandra Galetin
Drug Metabolism and Disposition July 1, 2010, 38 (7) 1147-1158; DOI: https://doi.org/10.1124/dmd.110.032649

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Research ArticleArticle

Prediction of Human Intestinal First-Pass Metabolism of 25 CYP3A Substrates from In Vitro Clearance and Permeability Data

Michael Gertz, Anthony Harrison, J. Brian Houston and Aleksandra Galetin
Drug Metabolism and Disposition July 1, 2010, 38 (7) 1147-1158; DOI: https://doi.org/10.1124/dmd.110.032649
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