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Bioactivation of Trimethoprim to Protein-Reactive Metabolites in Human Liver Microsomes

Jennifer L. Goldman, Yakov M. Koen, Steven A. Rogers, Kelin Li, James S. Leeder and Robert P. Hanzlik
Drug Metabolism and Disposition October 2016, 44 (10) 1603-1607; DOI: https://doi.org/10.1124/dmd.116.072041
Jennifer L. Goldman
Divisions of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Children’s Mercy Hospital, University of Missouri, Kansas City, Missouri (J.L.G., J.S.L.); Department of Medicinal Chemistry, University of Kansas School of Pharmacy, Lawrence, Kansas (Y.M.K., R.P.H.); Baker & McKenzie LLP, Dallas, Texas (S.A.R.); and Center for Integrative Chemical Biology and Drug Discovery, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (K.L.)
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Yakov M. Koen
Divisions of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Children’s Mercy Hospital, University of Missouri, Kansas City, Missouri (J.L.G., J.S.L.); Department of Medicinal Chemistry, University of Kansas School of Pharmacy, Lawrence, Kansas (Y.M.K., R.P.H.); Baker & McKenzie LLP, Dallas, Texas (S.A.R.); and Center for Integrative Chemical Biology and Drug Discovery, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (K.L.)
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Steven A. Rogers
Divisions of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Children’s Mercy Hospital, University of Missouri, Kansas City, Missouri (J.L.G., J.S.L.); Department of Medicinal Chemistry, University of Kansas School of Pharmacy, Lawrence, Kansas (Y.M.K., R.P.H.); Baker & McKenzie LLP, Dallas, Texas (S.A.R.); and Center for Integrative Chemical Biology and Drug Discovery, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (K.L.)
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Kelin Li
Divisions of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Children’s Mercy Hospital, University of Missouri, Kansas City, Missouri (J.L.G., J.S.L.); Department of Medicinal Chemistry, University of Kansas School of Pharmacy, Lawrence, Kansas (Y.M.K., R.P.H.); Baker & McKenzie LLP, Dallas, Texas (S.A.R.); and Center for Integrative Chemical Biology and Drug Discovery, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (K.L.)
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James S. Leeder
Divisions of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Children’s Mercy Hospital, University of Missouri, Kansas City, Missouri (J.L.G., J.S.L.); Department of Medicinal Chemistry, University of Kansas School of Pharmacy, Lawrence, Kansas (Y.M.K., R.P.H.); Baker & McKenzie LLP, Dallas, Texas (S.A.R.); and Center for Integrative Chemical Biology and Drug Discovery, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (K.L.)
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Robert P. Hanzlik
Divisions of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Children’s Mercy Hospital, University of Missouri, Kansas City, Missouri (J.L.G., J.S.L.); Department of Medicinal Chemistry, University of Kansas School of Pharmacy, Lawrence, Kansas (Y.M.K., R.P.H.); Baker & McKenzie LLP, Dallas, Texas (S.A.R.); and Center for Integrative Chemical Biology and Drug Discovery, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (K.L.)
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Abstract

The formation of drug-protein adducts via metabolic activation and covalent binding may stimulate an immune response or may result in direct cell toxicity. Protein covalent binding is a potentially pivotal step in the development of idiosyncratic adverse drug reactions (IADRs). Trimethoprim (TMP)-sulfamethoxazole (SMX) is a combination antibiotic that commonly causes IADRs. Recent data suggest that the contribution of the TMP component of TMP-SMX to IADRs may be underappreciated. We previously demonstrated that TMP is bioactivated to chemically reactive intermediates that can be trapped in vitro by N-acetyl cysteine (NAC), and we have detected TMP-NAC adducts (i.e., mercapturic acids) in the urine of patients taking TMP-SMX. However, the occurrence and extent of TMP covalent binding to proteins was unknown. To determine the ability of TMP to form protein adducts, we incubated [14C]TMP with human liver microsomes in the presence and absence of NADPH. We observed protein covalent binding that was NADPH dependent and increased with incubation time and concentration of both protein and TMP. The estimated covalent binding was 0.8 nmol Eq TMP/mg protein, which is comparable to the level of covalent binding for several other drugs that have been associated with covalent binding–induced toxicity and/or IADRs. NAC and selective inhibitors of CYP2B6 and CYP3A4 significantly reduced TMP covalent binding. These results demonstrate for the first time that TMP bioactivation can lead directly to protein adduct formation, suggesting that TMP has been overlooked as a potential contributor of TMP-SMX IADRs.

Footnotes

    • Received June 9, 2016.
    • Accepted July 22, 2016.
  • This research was supported in part by the National Institutes of Health National Center for Advancing Translational Sciences [Clinical and Translational Science Award KL2TR000119].

  • dx.doi.org/10.1124/dmd.116.072041.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (10)
Drug Metabolism and Disposition
Vol. 44, Issue 10
1 Oct 2016
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Rapid CommunicationShort Communication

Covalent Protein Binding of Trimethoprim In Vitro

Jennifer L. Goldman, Yakov M. Koen, Steven A. Rogers, Kelin Li, James S. Leeder and Robert P. Hanzlik
Drug Metabolism and Disposition October 1, 2016, 44 (10) 1603-1607; DOI: https://doi.org/10.1124/dmd.116.072041

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Rapid CommunicationShort Communication

Covalent Protein Binding of Trimethoprim In Vitro

Jennifer L. Goldman, Yakov M. Koen, Steven A. Rogers, Kelin Li, James S. Leeder and Robert P. Hanzlik
Drug Metabolism and Disposition October 1, 2016, 44 (10) 1603-1607; DOI: https://doi.org/10.1124/dmd.116.072041
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