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Research ArticleArticle

Purification and 1H NMR Spectroscopic Characterization of Phase II Metabolites of Tolfenamic Acid

Ulla Grove Sidelmann, Eyøhild Christiansen, Line Krogh, Claus Cornett and Jette Tjørnelund, and Steen Honoré Hansen
Drug Metabolism and Disposition June 1997, 25 (6) 725-731;
Ulla Grove Sidelmann
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Eyøhild Christiansen
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Line Krogh
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Claus Cornett
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Jette Tjørnelund, and Steen Honoré Hansen
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Abstract

Tolfenamic acid, an anti-inflammatory drug (NSAID), is metabolized in vivo to form several oxidative metabolites which are all conjugated with β-d-glucuronic acid. In this study, the metabolites of tolfenamic acid were identified by 1H nuclear magnetic resonance (NMR) spectroscopy in urine samples obtained on days 7 to 10 from a human volunteer after oral administration of 200 mg of the drug three times per day (steady-state plasma concentration). The metabolites of tolfenamic acid were initially concentrated by preparative solid phase extraction (PSPE) chromatography, thereby removing the endogenous polar compounds that are present in the urine. The individual metabolites were purified by preparative high performance liquid chromatography (HPLC) and then identified using 1H NMR. Both one- and two-dimensional NMR experiments were performed to identify the phase II metabolites of tolfenamic acid; the study shows the applicability of 1H NMR for the identification of drug metabolites in biological fluids. In addition to NMR analysis, two metabolites were also identified by mass spectrometry (MS). The glucuronides of the following parent compounds,N-(2-methyl-3-chlorophenyl)-anthranilic acid (T),N-(2-hydroxymethyl-3-chlorophenyl)-anthranilic acid (1),N-(2-hydroxymethyl-3-chloro-4-hydroxyphenyl)-anthranilic acid (2), N-(2-formyl-3-chlorophenyl) anthranilic acid (3),N-(2-methyl-3-chloro-4-hydroxyphenyl)-anthranilic acid (4),N-(2-methyl-3-chloro-5-hydroxyphenyl)-anthranilic acid (5), N-(2-carboxy-3-chlorophenyl)-anthranilic acid (6),N-(2-hydroxymethyl-3-chlorophenyl)-4-hydroxy-anthranilic acid (7),N-(2-methyl-3-chlorophenyl)-5-hydroxy-anthranilic acid (8),N-(2-methyl-3-chloro-4-metoxyphenyl)-anthranilic acid (9),N-(2-methyl-3-chlorophenyl)-4-hydroxy-anthranilic acid (10), andN-(2-methyl-4-hydroxyphenyl)-anthranilic acid (11) were identified. The phase II metabolites (5–11) had not previously been identified in urine from humans administered tolfenamic acid. The phase I metabolites of the glucuronides 7, 8, 10, and 11 were identified here for the first time. An HPLC method was developed that simultaneously separates all the phase II metabolites identified as well as some phase I metabolites in urine samples obtained after intake of tolfenamic acid.

Footnotes

  • Send reprint requests to: Ulla Grove Sidelmann, Department of Analytical and Pharmaceutical Chemistry, The Royal Danish School of Pharmacy, Universitetsparken 2, Dk-2100 Copenhagen, Dennmark.

  • Abbreviations used are::
    NSAID
    nonsteroidal anti-inflammatory drug
    TFA
    trifluoroacetic acid
    PSPE
    preparative solid phase extraction
    • Received December 4, 1996.
    • Accepted March 18, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 6
1 Jun 1997
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Research ArticleArticle

Purification and 1H NMR Spectroscopic Characterization of Phase II Metabolites of Tolfenamic Acid

Ulla Grove Sidelmann, Eyøhild Christiansen, Line Krogh, Claus Cornett and Jette Tjørnelund, and Steen Honoré Hansen
Drug Metabolism and Disposition June 1, 1997, 25 (6) 725-731;

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Research ArticleArticle

Purification and 1H NMR Spectroscopic Characterization of Phase II Metabolites of Tolfenamic Acid

Ulla Grove Sidelmann, Eyøhild Christiansen, Line Krogh, Claus Cornett and Jette Tjørnelund, and Steen Honoré Hansen
Drug Metabolism and Disposition June 1, 1997, 25 (6) 725-731;
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