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Research ArticleArticle

Physicochemical Property Space of Hepatobiliary Transport and Computational Models for Predicting Rat Biliary Excretion

Manthena V. S. Varma, George Chang, Yurong Lai, Bo Feng, Ayman F. El-Kattan, John Litchfield and Theunis C. Goosen
Drug Metabolism and Disposition August 2012, 40 (8) 1527-1537; DOI: https://doi.org/10.1124/dmd.112.044628
Manthena V. S. Varma
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George Chang
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Yurong Lai
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Bo Feng
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Ayman F. El-Kattan
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John Litchfield
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Theunis C. Goosen
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Abstract

Biliary excretion (BE) is a major elimination pathway, and its prediction is particularly important for optimization of systemic and/or target-site exposure of new molecular entities. The objective is to characterize the physicochemical space associated with hepatobiliary transport and rat BE and to develop in silico models. BE of 123 in-house compounds was obtained using the bile-duct cannulated rat model. Human and rat hepatic uptake transporters (hOATP1B1, hOATP1B3, hOATP2B1, and rOatp1b2) substrates (n = 183) were identified using transfected cells. Furthermore, the datasets were extended by adding BE of 163 compounds and 97 organic anion transporting polypeptide (OATP) substrates from the literature. Approximately 60% of compounds showing percentage of BE (%BE) ≥ 10 are anions, with mean BE of anions (36%) more than 3-fold higher than that of nonacids (11%). Compounds with %BE ≥ 10 are found to have high molecular mass, large polar surface area, more rotatable bonds, and high H-bond count, whereas the lipophilicity and passive membrane permeability are lower compared with compounds with %BE < 10. According to statistical analysis and principal component analysis, hOATPs and rOatp1b2 substrates showed physicochemical characteristics that were similar to those of the %BE ≥ 10 dataset. We further build categorical in silico models to predict rat BE, and the models (gradient boosting machine and scoring function) developed showed 80% predictability in identifying the rat BE bins (%BE ≥ 10 or < 10). In conclusion, the significant overlap of the property space of OATP substrates and rat BE suggests a predominant role of sinusoidal uptake transporters in biliary elimination. Categorical in silico models to predict rat BE were developed, and successful predictions were achieved.

Footnotes

  • This study was sponsored by Pfizer, Inc.

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

    http://dx.doi.org/10.1124/dmd.112.044628.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    BE
    biliary excretion
    DDI
    drug-drug interaction
    BDC
    bile-duct cannulated
    MRP
    multidrug resistance-associated protein
    BCRP
    breast cancer resistance protein
    OATP
    organic anion-transporting polypeptide
    2D
    two dimensional
    ACD
    Advanced Chemistry Development
    OCT
    organic cation transporter
    P-gp
    P-glycoprotein
    %BE
    percentage of biliary excretion
    CLb
    biliary clearance
    hOATP
    human organic anion-transporting polypeptide
    rOatp
    rat organic anion-transporting polypeptide
    LC/MS/MS
    liquid chromatography/tandem mass spectrometry
    PSA
    polar surface area
    RB
    rotatable bond
    HBA
    hydrogen bond acceptor
    HBD
    hydrogen bond donor
    RPSA
    relative polar surface area
    RRB
    relative rotatable bond
    ROC
    receiver operating characteristic
    AUC
    area under the curve
    GBM
    gradient-boosting machine
    PCA
    principal component analysis
    PC
    principal component
    QSAR
    quantitative structure-activity relationship.

  • Received January 16, 2012.
  • Accepted May 11, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (8)
Drug Metabolism and Disposition
Vol. 40, Issue 8
1 Aug 2012
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Research ArticleArticle

PHYSICOCHEMICAL SPACE OF HEPATOBILIARY TRANSPORT

Manthena V. S. Varma, George Chang, Yurong Lai, Bo Feng, Ayman F. El-Kattan, John Litchfield and Theunis C. Goosen
Drug Metabolism and Disposition August 1, 2012, 40 (8) 1527-1537; DOI: https://doi.org/10.1124/dmd.112.044628

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Research ArticleArticle

PHYSICOCHEMICAL SPACE OF HEPATOBILIARY TRANSPORT

Manthena V. S. Varma, George Chang, Yurong Lai, Bo Feng, Ayman F. El-Kattan, John Litchfield and Theunis C. Goosen
Drug Metabolism and Disposition August 1, 2012, 40 (8) 1527-1537; DOI: https://doi.org/10.1124/dmd.112.044628
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