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Research ArticleArticle

Quantitative Prediction of Intestinal Metabolism in Humans from a Simplified Intestinal Availability Model and Empirical Scaling Factor

Keitaro Kadono, Takafumi Akabane, Kenji Tabata, Katsuhiko Gato, Shigeyuki Terashita and Toshio Teramura
Drug Metabolism and Disposition July 2010, 38 (7) 1230-1237; DOI: https://doi.org/10.1124/dmd.109.029322
Keitaro Kadono
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Takafumi Akabane
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Kenji Tabata
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Katsuhiko Gato
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Shigeyuki Terashita
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Toshio Teramura
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Abstract

This study aimed to establish a practical and convenient method of predicting intestinal availability (Fg) in humans for highly permeable compounds at the drug discovery stage, with a focus on CYP3A4-mediated metabolism. We constructed a “simplified Fg model,” described using only metabolic parameters, assuming that passive diffusion is dominant when permeability is high and that the effect of transporters in epithelial cells is negligible. Five substrates for CYP3A4 (alprazolam, amlodipine, clonazepam, midazolam, and nifedipine) and four for both CYP3A4 and P-glycoprotein (P-gp) (nicardipine, quinidine, tacrolimus, and verapamil) were used as model compounds. Observed fraction of drug absorbed (FaFg) values for these compounds were calculated from in vivo pharmacokinetic (PK) parameters, whereas in vitro intestinal intrinsic clearance (CLint,intestine) was determined using human intestinal microsomes. The CLint,intestine for the model compounds corrected with that of midazolam was defined as CLm,index and incorporated into a simplified Fg model with empirical scaling factor. Regardless of whether the compound was a P-gp substrate, the FaFg could be reasonably fitted by the simplified Fg model, and the value of the empirical scaling factor was well estimated. These results suggest that the effects of P-gp on Fa and Fg are substantially minor, at least in the case of highly permeable compounds. Furthermore, liver intrinsic clearance (CLint,liver) can be used as a surrogate index of intestinal metabolism based on the relationship between CLint,liver and CLm,index. Fg can be easily predicted using a simplified Fg model with the empirical scaling factor, enabling more confident selection of drug candidates with desirable PK profiles in humans.

Footnotes

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

    doi:10.1124/dmd.109.029322.

  • ABBREVIATIONS:

    PK
    pharmacokinetic(s)
    Fa
    fraction of drug absorbed
    Fg
    intestinal availability
    Fh
    hepatic availability
    P-gp
    P-glycoprotein
    PSinf
    apparent influx clearance
    PSeff
    efflux clearance
    CLab
    absorption clearance
    CLm
    metabolic clearance
    Q
    luminal flow rate
    CLint,intestine
    intestinal intrinsic clearance
    CLm,index
    intestinal intrinsic clearance corrected with that of midazolam
    CLint,liver
    liver intrinsic clearance
    HIM
    human intestinal microsome
    HLM
    human liver microsome
    PAMPA
    parallel artificial membrane permeability assay
    DMSO
    dimethyl sulfoxide
    Papp
    apparent permeability coefficient
    LC/MS/MS
    liquid chromatography/tandem mass spectrometry
    P450
    cytochrome P450
    CLh
    hepatic clearance
    CLtot
    total body clearance
    CLr
    renal clearance
    Qh
    hepatic blood flow
    Rb
    blood-to-plasma concentration ratio
    SF
    scaling factor
    α
    empirical scaling factor.

  • Received July 14, 2009.
  • Accepted March 30, 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

Quantitative Prediction of Intestinal Metabolism in Humans from a Simplified Intestinal Availability Model and Empirical Scaling Factor

Keitaro Kadono, Takafumi Akabane, Kenji Tabata, Katsuhiko Gato, Shigeyuki Terashita and Toshio Teramura
Drug Metabolism and Disposition July 1, 2010, 38 (7) 1230-1237; DOI: https://doi.org/10.1124/dmd.109.029322

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Research ArticleArticle

Quantitative Prediction of Intestinal Metabolism in Humans from a Simplified Intestinal Availability Model and Empirical Scaling Factor

Keitaro Kadono, Takafumi Akabane, Kenji Tabata, Katsuhiko Gato, Shigeyuki Terashita and Toshio Teramura
Drug Metabolism and Disposition July 1, 2010, 38 (7) 1230-1237; DOI: https://doi.org/10.1124/dmd.109.029322
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