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Research ArticleArticle

Effect of Selective Phase II Enzyme Inducers on Glucuronidation of Benoxaprofen in Rats

Jennifer Q. Dong, Amy S. Etheridge and Philip C. Smith
Drug Metabolism and Disposition December 1999, 27 (12) 1423-1428;
Jennifer Q. Dong
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Amy S. Etheridge
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Philip C. Smith
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Abstract

The induction of benoxaprofen (BNX) glucuronidation in rats by intragastric administration of three nitrogen heterocycles (quinoline, 2,2′-dipyridyl, or 1,7-phenanthroline at 75 mg/kg daily for 3 days) has been investigated. BNX was administered i.v. at a dose of 20 mg/kg to bile-cannulated rats that had been induced. Blood and bile were collected over 8 h. Liver tissues were also collected at the end of the 8-h study and used to examine conjugation activity of BNX by UDP-glucuronosyl transferases and cytochrome P-450 enzyme activities in vitro. Two methods were used to characterize the true metabolic formation rates of the labile benoxaprofen glucuronide conjugate in vitro, which gave comparable mean values forKM and Vmax. There appeared to be a trend of increase of theVmax of BNX glucuronidation in rat liver microsomes by all three nitrogen heterocycles; however, the induction was only significant with 1,7-phenanthroline.KM was not noticeably altered by any of the three inducers. No change of measured hepatic microsomal cytochrome P-450 activities in the rat was found. BNX glucuronidation in rats in vivo was increased by all three nitrogen heterocycles with 1,7-phenanthroline more effective than quinoline and 2,2′-dipyridyl. The use of nitrogen heterocycles provides a means to modulate exposure to labile, reactive acyl glucuronides in vivo without apparent changes in oxidative metabolism.

Footnotes

  • Send reprint requests to: Dr. Philip C. Smith, Division of Drug Delivery and Disposition, CB#7360, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360. E-mail: pcs{at}emailunc.edu

  • ↵1 Present address: CB#7360, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360.

  • ↵2 Present address: Research Triangle Institute, Research Triangle Park, NC 27709.

  • This study was supported by National Institutes of Health Grant GM41828.

  • Abbreviations used are::
    UGT
    UDP-glucuronosyl transferase
    BNX
    benoxaprofen
    BNX-G
    benoxaprofen glucuronide conjugate
    CYP
    cytochrome P-450
    QO
    quinoline
    PH
    1,7-phenanthroline
    DP
    2,2′-dipyridyl
    TFA
    trifluoroacetic acid
    SA
    saccharic acid-1, 4-lactone
    PMSF
    phenylmethylsulfonyl fluoride
    AUC0→8hr
    area under the plasma concentration curve up to 8 h
    Ae,bile,0→8hr
    cumulative biliary excretion up to 8 h
    Clf,bile,app
    apparent biliary formation clearance of BNX-G
    • Received April 26, 1999.
    • Accepted August 19, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (12)
Drug Metabolism and Disposition
Vol. 27, Issue 12
1 Dec 1999
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Research ArticleArticle

Effect of Selective Phase II Enzyme Inducers on Glucuronidation of Benoxaprofen in Rats

Jennifer Q. Dong, Amy S. Etheridge and Philip C. Smith
Drug Metabolism and Disposition December 1, 1999, 27 (12) 1423-1428;

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Research ArticleArticle

Effect of Selective Phase II Enzyme Inducers on Glucuronidation of Benoxaprofen in Rats

Jennifer Q. Dong, Amy S. Etheridge and Philip C. Smith
Drug Metabolism and Disposition December 1, 1999, 27 (12) 1423-1428;
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