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Research ArticleArticle

Effect of Albumin on Human Liver Microsomal and Recombinant CYP1A2 Activities: Impact on In Vitro-In Vivo Extrapolation of Drug Clearance

Nitsupa Wattanachai, Wichittra Tassaneeyakul, Andrew Rowland, David J. Elliot, Kushari Bowalgaha, Kathleen M. Knights and John O. Miners
Drug Metabolism and Disposition May 2012, 40 (5) 982-989; DOI: https://doi.org/10.1124/dmd.111.044057
Nitsupa Wattanachai
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Wichittra Tassaneeyakul
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Andrew Rowland
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David J. Elliot
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Kushari Bowalgaha
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Kathleen M. Knights
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John O. Miners
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Abstract

Long-chain unsaturated fatty acids inhibit several cytochrome P450 and UDP-glucuronosyltransferase (UGT) enzymes involved in drug metabolism, including CYP2C8, CYP2C9, UGT1A9, UGT2B4, and UGT2B7. Bovine serum albumin (BSA) enhances these cytochrome P450 and UGT activities by sequestering fatty acids that are released from membranes, especially with human liver microsomes (HLM) as the enzyme source. Here, we report the effects of BSA on CYP1A2-catalyzed phenacetin (PHEN) O-deethylation and lidocaine (LID) N-deethylation using HLM and Escherichia coli-expressed recombinant human CYP1A2 (rCYP1A2) as the enzyme sources. BSA (2% w/v) reduced (p < 0.05) the Km values of the high-affinity components of human liver microsomal PHEN and LID deethylation by approximately 70%, without affecting Vmax. The Km (or S50) values for PHEN and LID deethylation by rCYP1A2 were reduced to a similar extent. A fatty acid mixture, comprising 3 μM concentrations each of oleic acid and linoleic acid plus 1.5 μM arachidonic acid, doubled the Km value for PHEN O-deethylation by rCYP1A2. Inhibition was reversed by the addition of BSA. Ki values for the individual fatty acids ranged from 4.7 to 16.7 μM. Single-point in vitro-in vivo extrapolation (IV-IVE) based on the human liver microsomal kinetic parameters obtained in the presence, but not absence, of BSA predicted in vivo hepatic clearances of PHEN O-deethylation and LID N-deethylation that were comparable to values reported in humans, although in vivo intrinsic clearances were underpredicted. Prediction of the in vivo clearances of the CYP1A2 substrates observed here represents an improvement on other experimental systems used for IV-IVE.

Footnotes

  • This study was supported by the National Health and Medical Research Council of Australia [Grant 480417]; the Thailand Research Fund; the Higher Education Research Promotion and National Research University Project of Thailand; and the Office of the Higher Education Commission through the Health Cluster (SHeP-GMS), Khon Kaen University. N.W. and W.T. received support from the Thailand Research Fund through the Royal Golden Ph.D. Program [PHD/0167/2548].

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

    http://dx.doi.org/10.1124/dmd.111.044057.

  • ABBREVIATIONS:

    CLH
    hepatic clearance
    P450
    cytochrome P450
    UGT
    UDP-glucuronosyltransferase
    IV-IVE
    in vitro-in vivo extrapolation
    BSA
    bovine serum albumin
    HLM
    human liver microsomes
    PHEN
    phenacetin
    LID
    lidocaine
    rCYP1A2
    recombinant human CYP1A2
    APAP
    acetaminophen
    MEGX
    monoethylglycinexylidide
    HPLC
    high-performance liquid chromatography
    FAM
    fatty acid mixture.

  • Received November 30, 2011.
  • Accepted February 7, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (5)
Drug Metabolism and Disposition
Vol. 40, Issue 5
1 May 2012
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Research ArticleArticle

EFFECT OF ALBUMIN ON HUMAN CYP1A2 ACTIVITY

Nitsupa Wattanachai, Wichittra Tassaneeyakul, Andrew Rowland, David J. Elliot, Kushari Bowalgaha, Kathleen M. Knights and John O. Miners
Drug Metabolism and Disposition May 1, 2012, 40 (5) 982-989; DOI: https://doi.org/10.1124/dmd.111.044057

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Research ArticleArticle

EFFECT OF ALBUMIN ON HUMAN CYP1A2 ACTIVITY

Nitsupa Wattanachai, Wichittra Tassaneeyakul, Andrew Rowland, David J. Elliot, Kushari Bowalgaha, Kathleen M. Knights and John O. Miners
Drug Metabolism and Disposition May 1, 2012, 40 (5) 982-989; DOI: https://doi.org/10.1124/dmd.111.044057
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