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Research ArticleArticle

In Vitro Hepatic Oxidative Biotransformation of Trimethoprim

Jennifer L. Goldman, J. Steven Leeder, Leon Van Haandel and Robin E. Pearce
Drug Metabolism and Disposition September 2015, 43 (9) 1372-1380; DOI: https://doi.org/10.1124/dmd.115.065193
Jennifer L. Goldman
Divisions of Clinical Pharmacology, Toxicology and Therapeutic Innovation (J.L.G., J.S.L., L.V.H., R.E.P.) and Infectious Diseases (J.L.G.), Departments of Pediatrics (J.L.G., J.S.L., L.V.H., R.E.P.) and Pharmacology (J.S.L. R.E.P.), Children’s Mercy Hospital, University of Missouri, Kansas City, Missouri
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J. Steven Leeder
Divisions of Clinical Pharmacology, Toxicology and Therapeutic Innovation (J.L.G., J.S.L., L.V.H., R.E.P.) and Infectious Diseases (J.L.G.), Departments of Pediatrics (J.L.G., J.S.L., L.V.H., R.E.P.) and Pharmacology (J.S.L. R.E.P.), Children’s Mercy Hospital, University of Missouri, Kansas City, Missouri
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Leon Van Haandel
Divisions of Clinical Pharmacology, Toxicology and Therapeutic Innovation (J.L.G., J.S.L., L.V.H., R.E.P.) and Infectious Diseases (J.L.G.), Departments of Pediatrics (J.L.G., J.S.L., L.V.H., R.E.P.) and Pharmacology (J.S.L. R.E.P.), Children’s Mercy Hospital, University of Missouri, Kansas City, Missouri
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Robin E. Pearce
Divisions of Clinical Pharmacology, Toxicology and Therapeutic Innovation (J.L.G., J.S.L., L.V.H., R.E.P.) and Infectious Diseases (J.L.G.), Departments of Pediatrics (J.L.G., J.S.L., L.V.H., R.E.P.) and Pharmacology (J.S.L. R.E.P.), Children’s Mercy Hospital, University of Missouri, Kansas City, Missouri
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This article has a correction. Please see:

  • Correction to “In Vitro Hepatic Oxidative Biotransformation of Trimethoprim” - April 01, 2019

Abstract

Trimethoprim (TMP) has been widely used since the 1960s, both alone and in combination with sulfamethoxazole. Unfortunately, information regarding the role that cytochrome P450 enzymes (P450s) play in the formation of TMP primary metabolites is scarce. Hence, we undertook in vitro studies to identify and more fully characterize the P450s that catalyze formation of six TMP primary metabolites: TMP 1-N-oxide (1-NO-TMP) and 3-N-oxide (3-NO-TMP), 3′- and 4′-desmethyl-TMP, a benzylic alcohol (Cα-OH-TMP), and an N-acetyl cysteine (NAC) adduct of TMP (Cα-NAC-TMP). Formation kinetics for each TMP metabolite in human liver microsomes (HLMs) were consistent with single-enzyme Michaelis-Menten kinetics, and Km values were markedly above (≥10-fold) the therapeutic concentrations of TMP (50 µM). The combined results from correlation studies between rates of metabolite formation and marker P450 activities in a panel of HLMs along with inhibition studies utilizing selective P450 inhibitors incubated with pooled HLMs suggested that 1-NO-TMP, Cα-NAC-TMP, and Cα-OH-TMP were predominantly formed by CYP3A4. In contrast, 3-NO-TMP was formed predominantly by CYP1A2 in HLMs and inhibited by α-naphthoflavone. 4′-Desmethyl-TMP, which is believed to be a reactive TMP metabolite precursor, was formed by several P450s, including CYP3A4, correlated with multiple P450 activities, but was inhibited primarily by ketoconazole (up to 50%), suggesting that CYP3A4 makes a major contribution to TMP 4′-demethylation. TMP 3′-demethylation was catalyzed by multiple P450s, including CYP2C9, correlated with CYP2C9 activity, and was inhibited by sulfaphenazole (up to 40%). Overall, CYP2C9 and CYP3A4 appear to be the most significant contributors to TMP primary metabolism.

Footnotes

    • Received May 1, 2015.
    • Accepted July 2, 2015.
  • dx.doi.org/10.1124/dmd.115.065193.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (9)
Drug Metabolism and Disposition
Vol. 43, Issue 9
1 Sep 2015
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Research ArticleArticle

Primary Biotransformation of Trimethoprim In Vitro

Jennifer L. Goldman, J. Steven Leeder, Leon Van Haandel and Robin E. Pearce
Drug Metabolism and Disposition September 1, 2015, 43 (9) 1372-1380; DOI: https://doi.org/10.1124/dmd.115.065193

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Research ArticleArticle

Primary Biotransformation of Trimethoprim In Vitro

Jennifer L. Goldman, J. Steven Leeder, Leon Van Haandel and Robin E. Pearce
Drug Metabolism and Disposition September 1, 2015, 43 (9) 1372-1380; DOI: https://doi.org/10.1124/dmd.115.065193
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