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Research ArticleArticle

Quaternary Ammonium-Linked Glucuronidation of 1-Substituted Imidazoles by Liver Microsomes: Interspecies Differences and Structure-Metabolism Relationships

Sarvesh C. Vashishtha, Edward M. Hawes, Denis J. McCann, Omar Ghosheh and Lawrence Hogg
Drug Metabolism and Disposition October 2002, 30 (10) 1070-1076; DOI: https://doi.org/10.1124/dmd.30.10.1070
Sarvesh C. Vashishtha
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Edward M. Hawes
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Denis J. McCann
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Omar Ghosheh
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Lawrence Hogg
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Abstract

N-Glucuronidation at an aromatic tertiary amine of 5-membered polyaza ring systems was investigated for a model series of eight 1-substituted imidazoles in liver microsomes from five species. The major objectives were to investigate substrate specificities of the series in human microsomes and interspecies variation for the prototype molecule, 1-phenylimidazole. The formed quaternary ammonium-linked metabolites were characterized by positive ion electrospray mass spectrometry. The incubation conditions for theN-glucuronidation of 1-substituted imidazoles were optimized; where for membrane disrupting agents, alamethicin was more effective than the detergents examined. The need to optimize alamethicin concentration was indicated by 4-fold interspecies variation in optimal concentration and by a change in effect from removal of glucuronidation latency to inhibition on increasing concentration. For the four species with quantifiableN-glucuronidation of 1-phenylimidazole, there were 8- and 18-fold variations in the determined apparentKm (range, 0.63 to 4.8 mM) andVmax (range, 0.08 to 1.4 nmol/min/mg of protein) values, respectively. The apparent clearance values (Vmax/Km) were in the following order: human ≅ guinea pig ≅ rabbit > rat ≅ dog (no metabolite detected). Monophasic kinetics were observed for theN-glucuronidation of seven substrates by human liver microsomes, which suggests that one enzyme is involved in each metabolic catalysis. No N-glucuronidation was observed for the substrate containing the para-phenyl substituent with the largest electron withdrawing effect, 1-(4-nitrophenyl)imidazole. Linear correlation analyses between apparent microsomal kinetics and substrate physicochemical parameters revealed significant correlations between Kmand lipophilicity (πpara or log P values) and betweenVmax/Km and both electronic properties (ςpara value) and pKa.

Footnotes

  • ↵1 Current address: Wyeth Research, 500 Arcola Road, Collegeville, PA 19426-3930.

  • ↵2 Current address: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285.

  • This work was supported by an AstraZeneca academic grant (to E.M.H. and D.J.M.), a Canadian Institutes of Health Research operating grant (MOP-36513 to E.M.H.), and a Health Services Utilization and Research Commission of Saskatchewan Research Fellowship (to O.G.).

  • Abbreviations used are::
    UGT
    UDP-glucuronosyltransferase
    N+-glucuronide
    quaternary ammonium-linked glucuronide metabolite
    SMR
    structure-metabolism relationships
    CHAPS
    3-[(3-cholamidopropyl)dimethylamino]-1-propanesulfonate
    UDPGA
    UDP-glucuronic acid
    HPLC
    high-performance liquid chromatography
    ESI
    electrospray ionization
    MS
    mass spectrometry
    APCI
    atmospheric pressure chemical ionization
    • Received February 15, 2002.
    • Accepted June 19, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (10)
Drug Metabolism and Disposition
Vol. 30, Issue 10
1 Oct 2002
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Research ArticleArticle

Quaternary Ammonium-Linked Glucuronidation of 1-Substituted Imidazoles by Liver Microsomes: Interspecies Differences and Structure-Metabolism Relationships

Sarvesh C. Vashishtha, Edward M. Hawes, Denis J. McCann, Omar Ghosheh and Lawrence Hogg
Drug Metabolism and Disposition October 1, 2002, 30 (10) 1070-1076; DOI: https://doi.org/10.1124/dmd.30.10.1070

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Research ArticleArticle

Quaternary Ammonium-Linked Glucuronidation of 1-Substituted Imidazoles by Liver Microsomes: Interspecies Differences and Structure-Metabolism Relationships

Sarvesh C. Vashishtha, Edward M. Hawes, Denis J. McCann, Omar Ghosheh and Lawrence Hogg
Drug Metabolism and Disposition October 1, 2002, 30 (10) 1070-1076; DOI: https://doi.org/10.1124/dmd.30.10.1070
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