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Research ArticleArticle

Amide Hydrolysis of a Novel Chemical Series of Microsomal Prostaglandin E Synthase-1 Inhibitors Induces Kidney Toxicity in the Rat

Johan Bylund, Anita Annas, Dennis Hellgren, Sivert Bjurström, Håkan Andersson and Alexander Svanhagen
Drug Metabolism and Disposition March 2013, 41 (3) 634-641; DOI: https://doi.org/10.1124/dmd.112.048983
Johan Bylund
Drug Metabolism and Pharmacokinetics, CNSP iMed Science (J.B.), and Safety Assessment (A.A., D.H., S.B., H.A., A.S.), AstraZeneca R&D, Innovative Medicines, Södertälje, Sweden; and Department of Pharmaceutical Biosciences, Uppsala Biomedical Centre, Uppsala University, Uppsala, Sweden (J.B.)
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Anita Annas
Drug Metabolism and Pharmacokinetics, CNSP iMed Science (J.B.), and Safety Assessment (A.A., D.H., S.B., H.A., A.S.), AstraZeneca R&D, Innovative Medicines, Södertälje, Sweden; and Department of Pharmaceutical Biosciences, Uppsala Biomedical Centre, Uppsala University, Uppsala, Sweden (J.B.)
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Dennis Hellgren
Drug Metabolism and Pharmacokinetics, CNSP iMed Science (J.B.), and Safety Assessment (A.A., D.H., S.B., H.A., A.S.), AstraZeneca R&D, Innovative Medicines, Södertälje, Sweden; and Department of Pharmaceutical Biosciences, Uppsala Biomedical Centre, Uppsala University, Uppsala, Sweden (J.B.)
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Sivert Bjurström
Drug Metabolism and Pharmacokinetics, CNSP iMed Science (J.B.), and Safety Assessment (A.A., D.H., S.B., H.A., A.S.), AstraZeneca R&D, Innovative Medicines, Södertälje, Sweden; and Department of Pharmaceutical Biosciences, Uppsala Biomedical Centre, Uppsala University, Uppsala, Sweden (J.B.)
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Håkan Andersson
Drug Metabolism and Pharmacokinetics, CNSP iMed Science (J.B.), and Safety Assessment (A.A., D.H., S.B., H.A., A.S.), AstraZeneca R&D, Innovative Medicines, Södertälje, Sweden; and Department of Pharmaceutical Biosciences, Uppsala Biomedical Centre, Uppsala University, Uppsala, Sweden (J.B.)
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Alexander Svanhagen
Drug Metabolism and Pharmacokinetics, CNSP iMed Science (J.B.), and Safety Assessment (A.A., D.H., S.B., H.A., A.S.), AstraZeneca R&D, Innovative Medicines, Södertälje, Sweden; and Department of Pharmaceutical Biosciences, Uppsala Biomedical Centre, Uppsala University, Uppsala, Sweden (J.B.)
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Abstract

A novel microsomal prostaglandin E synthase 1 (mPGES-1) inhibitor induced kidney injury at exposures representing less than 4 times the anticipated efficacious exposure in man during a 7-day toxicity study in rats. The findings consisted mainly of tubular lesions and the presence of crystalline material and increases in plasma urea and creatinine. In vitro and in vivo metabolic profiling generated a working hypothesis that a bis-sulfonamide metabolite (determined M1) formed by amide hydrolysis caused this toxicity. To test this hypothesis, rats were subjected to a 7-day study and were administered the suspected metabolite and two low-potency mPGES-1 inhibitor analogs, where amide hydrolysis was undetectable in rat hepatocyte experiments. The results suggested that compounds with a reduced propensity to undergo amide hydrolysis, thus having less ability to form M1, reduced the risk of inducing kidney toxicity. Rats treated with M1 alone showed no histopathologic change in the kidney, which was likely related to underexposure to M1. To circumvent rat kidney toxicity, we identified a potent mPGES-1 inhibitor with a low propensity for amide hydrolysis and superior rat pharmacokinetic properties. A subsequent 14-day rat toxicity study showed that this compound was associated with kidney toxicity at 42, but not 21, times the anticipated efficacious exposure in humans. In conclusion, by including metabolic profiling and exploratory rat toxicity studies, a new and active mPGES-1 inhibitor with improved margins to chemically induced kidney toxicity in rats has been identified.

Footnotes

  • dx.doi.org/10.1124/dmd.112.048983.

  • Received September 10, 2012.
  • Accepted January 2, 2013.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (3)
Drug Metabolism and Disposition
Vol. 41, Issue 3
1 Mar 2013
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Research ArticleArticle

Amide Hydrolysis-Induced Kidney Toxicity

Johan Bylund, Anita Annas, Dennis Hellgren, Sivert Bjurström, Håkan Andersson and Alexander Svanhagen
Drug Metabolism and Disposition March 1, 2013, 41 (3) 634-641; DOI: https://doi.org/10.1124/dmd.112.048983

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Research ArticleArticle

Amide Hydrolysis-Induced Kidney Toxicity

Johan Bylund, Anita Annas, Dennis Hellgren, Sivert Bjurström, Håkan Andersson and Alexander Svanhagen
Drug Metabolism and Disposition March 1, 2013, 41 (3) 634-641; DOI: https://doi.org/10.1124/dmd.112.048983
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