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Research ArticleArticle

The Glucuronidation of Morphine by Dog Liver Microsomes: Identification of Morphine-6-O-Glucuronide

Christopher King, Bernita Finley and Ronald Franklin
Drug Metabolism and Disposition June 2000, 28 (6) 661-663;
Christopher King
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Bernita Finley
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Ronald Franklin
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Abstract

Canines are used extensively in the pharmaceutical industry for the preclinical screening of novel therapeutics, yet comparatively little is known about the phase 2 metabolism in this species. In humans, morphine is known to undergo extensive metabolism by glucuronidation, and the UDP-glucuronosyltransferase isoform, which catalyzes the formation of morphine-3-O-glucuronide and morphine-6-O-glucuronide is UGT2B7. This study was designed to investigate the glucuronidation of morphine using dog liver microsomes. Liver microsomes from beagle dogs catalyzed the glucuronidation of morphine-3(and 6)-O-glucuronide at rates 4 to 10 times that of rhesus monkey and human liver microsomes. The Km of morphine using beagle dog liver microsomes was ∼270 μM, which is similar to that found for expressed human UGT2B7. The Vmax for morphine, using dog liver microsomes, was 27 nmol/min/mg of protein. Flunitrazepam inhibited the glucuronidation of morphine in dog liver microsomes, and the Ki was 40 μM, which is similar to human UGT2B7 for other substrates. The effects of detergents were also investigated with dog liver microsomes, and Brij 35 and Brij 58 were found to be the best detergents to use for maximal activation of the dog liver morphine UGT. These studies suggest that dog has a UGT2B isoform similar to human UGT2B7.

Footnotes

  • Send reprint requests to: Christopher King, Ph.D., Merck & Co., P.O. Box 2000, RY80-A9 Rahway, NJ 07065. E-mail:christopher_king{at}merck.com

  • Abbreviations used are::
    UGT
    UDP-glucuronosyltransferase
    NMG
    nonanoyl-N-methylglucamide
    OTG
    octyl symbol 98 β-thioglucopyranoside
    OBG
    octyl symbol 98 β-glucoside
    CHAPS
    3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate
    CHAPSO
    3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonate
    UDPGA
    UDP-glucuronic acid
    M3G
    morphine-3-O-glucuronide
    M6G
    morphine-6-O-glucuronide
    FNZ
    flunitrazepam
    • Received December 20, 1999.
    • Accepted February 28, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (6)
Drug Metabolism and Disposition
Vol. 28, Issue 6
1 Jun 2000
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Research ArticleArticle

The Glucuronidation of Morphine by Dog Liver Microsomes: Identification of Morphine-6-O-Glucuronide

Christopher King, Bernita Finley and Ronald Franklin
Drug Metabolism and Disposition June 1, 2000, 28 (6) 661-663;

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Research ArticleArticle

The Glucuronidation of Morphine by Dog Liver Microsomes: Identification of Morphine-6-O-Glucuronide

Christopher King, Bernita Finley and Ronald Franklin
Drug Metabolism and Disposition June 1, 2000, 28 (6) 661-663;
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