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Research ArticleArticle

Down-Regulation of Hepatic CYP3A and CYP2C Mediated Metabolism in Rats with Moderate Chronic Kidney Disease

Thomas J. Velenosi, Angel Y. N. Fu, Shuhua Luo, Hao Wang and Bradley L. Urquhart
Drug Metabolism and Disposition August 2012, 40 (8) 1508-1514; DOI: https://doi.org/10.1124/dmd.112.045245
Thomas J. Velenosi
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Angel Y. N. Fu
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Shuhua Luo
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Hao Wang
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Bradley L. Urquhart
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Abstract

Expression and activity of drug-metabolizing enzymes are decreased in severe kidney disease; however, only a small percentage of patients with chronic kidney disease (CKD) are at the final stage of the disease. This study aimed to determine the changes in drug-metabolizing enzyme function and expression in rats with varying degrees of kidney disease. Sprague-Dawley rats were subjected to surgical procedures that allowed the generation of three distinct models of kidney function: normal kidney function, moderate kidney function, and severe kidney disease. Forty-two days after surgery, rats were sacrificed and hepatic CYP3A and CYP2C expression was determined. In addition, enzymatic activity was determined in liver microsomes by evaluating midazolam (CYP3A), testosterone (CYP3A and CYP2C), and tolbutamide (CYP2C) enzyme kinetics. Both moderate and severe kidney disease were associated with a reduction in CYP3A2 and CYP2C11 expression (p < 0.05). Likewise, moderate kidney disease resulted in more than a 60% decrease in enzyme activity (Vmax) for CYP2C11 and CYP3A, compared with controls (p < 0.05). When the degree of kidney disease was correlated with metabolic activity, an exponential decline in CYP2C- and CYP3A-mediated metabolism was observed. Our results demonstrate that CYP3A and CYP2C expression and activity are decreased in both moderate and severe CKD. Our data suggest that drug metabolism is significantly decreased in the earlier stages of CKD and imply that patients with moderate CKD may be subject to unpredictable pharmacokinetics.

Footnotes

  • This work was supported by the Natural Sciences and Engineering Research Council of Canada Discovery Grants Program [Grant 386569-2010]; and a Canada Graduate Scholarship Masters award.

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

    http://dx.doi.org/10.1124/dmd.112.045245.

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

  • ABBREVIATIONS:

    CKD
    chronic kidney disease
    P450
    cytochrome P450
    KEEP
    Kidney Early Evaluation Program
    NHANES
    National Health and Nutrition Examination Survey
    PCR
    polymerase chain reaction
    CT
    cycle threshold
    HRP
    horseradish peroxidase
    UPLC-PDA
    ultraperformance liquid chromatography with photodiode array detection
    ESRD
    end-stage renal disease
    NF
    nuclear factor.

  • Received February 29, 2012.
  • Accepted May 9, 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

DRUG METABOLISM IN CKD

Thomas J. Velenosi, Angel Y. N. Fu, Shuhua Luo, Hao Wang and Bradley L. Urquhart
Drug Metabolism and Disposition August 1, 2012, 40 (8) 1508-1514; DOI: https://doi.org/10.1124/dmd.112.045245

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Research ArticleArticle

DRUG METABOLISM IN CKD

Thomas J. Velenosi, Angel Y. N. Fu, Shuhua Luo, Hao Wang and Bradley L. Urquhart
Drug Metabolism and Disposition August 1, 2012, 40 (8) 1508-1514; DOI: https://doi.org/10.1124/dmd.112.045245
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