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Research ArticleArticle

Interaction of Human Serum Albumin with the Electrophilic Metabolite 1-O-Gemfibrozil-β-d-Glucuronide

Benedetta C. Sallustio, Barbara A. Fairchild and Peter R. Pannall
Drug Metabolism and Disposition January 1997, 25 (1) 55-60;
Benedetta C. Sallustio
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Barbara A. Fairchild
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Peter R. Pannall
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Abstract

Acyl glucuronides are electrophilic metabolites that are readily hydrolyzed, undergo intramolecular rearrangement, and bind covalently to endogenous proteins. Gemfibrozil is a fibrate lipid-lowering agent that is extensively metabolized to an acyl glucuronide conjugate in humans. The aims of this study were to examine the interactions of 1-O-gemfibrozil-β-d-glucuronide with human serum albumin. The degradation of 1-O-gemfibrozil-β-d-glucuronide (∼200 μM) was examined in vitro during incubations at 37°C with phosphate buffer (pH 7.4 or 9.0), solutions of human serum albumin (pH 7.4), or fresh human plasma (pH 7.4). The effects of diazepam, oxyphenbutazone, and gemfibrozil on the degradation of 1-O-gemfibrozil-β-d-glucuronide, and its reversible binding to albumin were also studied. A pilot in vivo study was performed on two patient volunteers administered 1 g/day po gemfibrozil. 1-O-Gemfibrozil-β-d-glucuronide was unstable, with degradation half-lives in buffer of 4.1 hr and 44 hr at pH 9.0 and 7.4, respectively; and 8.5 hr and 5.5 hr in pH 7.4 solutions of human serum albumin or fresh plasma, respectively. Degradation was dependent on pH and the presence of albumin, which seemed to accelerate the intramolecular rearrangement and hydrolysis of the conjugate. 1-O-Gemfibrozil-β-d-glucuronide was highly reversibly bound to albumin, with a mean unbound fraction of 0.028, and its degradation seemed to be related to the degree of reversible binding. Hydrolysis and covalent binding were associated with the site II binding domain on albumin, because only diazepam inhibited these reactions. However, intramolecular rearrangement was increased when binding to the site I domain was inhibited. Covalent binding was also detected in vivo to human plasma proteins. The half-life of the gemfibrozil-protein adducts was 2.5–3 days. Albumin plays an important role in the disposition of acyl glucuronides by acting as:i) a transporter protein; ii) a potential catalyst for their degradation and, therefore, clearance; andiii) a target for covalent adduct formation.

Footnotes

  • Send reprint requests to: Dr. Benedetta C. Sallustio, Department of Clinical Pharmacology, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville 5011, South Australia.

  • This study was supported by the National Heart Foundation of Australia.

    • Received March 26, 1996.
    • Accepted September 26, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 1
1 Jan 1997
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Research ArticleArticle

Interaction of Human Serum Albumin with the Electrophilic Metabolite 1-O-Gemfibrozil-β-d-Glucuronide

Benedetta C. Sallustio, Barbara A. Fairchild and Peter R. Pannall
Drug Metabolism and Disposition January 1, 1997, 25 (1) 55-60;

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Research ArticleArticle

Interaction of Human Serum Albumin with the Electrophilic Metabolite 1-O-Gemfibrozil-β-d-Glucuronide

Benedetta C. Sallustio, Barbara A. Fairchild and Peter R. Pannall
Drug Metabolism and Disposition January 1, 1997, 25 (1) 55-60;
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