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Research ArticleArticle

The Development of UDP-Glucuronosyltransferases 1A1 and 1A6 in the Pediatric Liver

Shogo J. Miyagi and Abby C. Collier
Drug Metabolism and Disposition May 2011, 39 (5) 912-919; DOI: https://doi.org/10.1124/dmd.110.037192
Shogo J. Miyagi
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Abby C. Collier
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Abstract

UDP-glucuronosyltransferases (UGTs) are critical for the metabolism and clearance of drugs, chemicals, and hormones. The development of UGT1A1 and 1A6 was studied in 50 pediatric liver samples using bilirubin, serotonin activity assays, and Western blot as well as pharmacokinetic scaling. UGT activity developed age dependently in pediatric liver. Maximal activity of 0.7690 nmol · min · −1 mg protein−1 was observed for UGT1A1 at 3.8 months. For UGT1A6, activity matured at 14 months (4.737 nmol · min · −1mg protein−1). Protein expression was not age-dependent, and activities did not correlate to protein levels for either enzyme. The in vitro activities were used to calculate normalized hepatic clearances using both allometric scaling and a physiologically based pharmacokinetic model. For UGT1A1, allometry predicted normalized adult clearances of 0.0070 l · h−1 · kg−1 at 3.0 (well stirred) and 2.8 years (parallel tube), whereas the Simcyp model showed normalized clearances of 0.0079 l · h−1 · kg−1 at 2.6 (well stirred) and 2.5 years (parallel tube). For UGT1A6, only the Simcyp well stirred model converged at 0.3524 l · h−1 · kg−1 at 12.6 months. These data imply independent regulation of UGT1A1 and 1A6 where activity has matured after 6 months to 1 year. Total hepatic clearance of substances mediated by these enzymes may mature concurrently or take longer because of other physiological factors. Late development of UGT enzymes may contribute to chemical, drug, and environmental toxicity.

Footnotes

  • This work was supported by the National Institutes of Health National Center for Research Resources [Grant RR024206] (Project 4); and the Alana Dung Foundation [Grant 124-8090-4].

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

    doi:10.1124/dmd.110.037192.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    ELISA
    enzyme-linked immunosorbent assay
    fu
    fraction unbound
    MPPGL
    microsomal protein per gram liver
    Sy.x
    S.E. of estimate
    UGT
    UDP-glucuronosyltransferase
    CI
    confidence interval.

  • Received November 11, 2010.
  • Accepted January 25, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (5)
Drug Metabolism and Disposition
Vol. 39, Issue 5
1 May 2011
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Research ArticleArticle

The Development of UDP-Glucuronosyltransferases 1A1 and 1A6 in the Pediatric Liver

Shogo J. Miyagi and Abby C. Collier
Drug Metabolism and Disposition May 1, 2011, 39 (5) 912-919; DOI: https://doi.org/10.1124/dmd.110.037192

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Research ArticleArticle

The Development of UDP-Glucuronosyltransferases 1A1 and 1A6 in the Pediatric Liver

Shogo J. Miyagi and Abby C. Collier
Drug Metabolism and Disposition May 1, 2011, 39 (5) 912-919; DOI: https://doi.org/10.1124/dmd.110.037192
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