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Analytical Power of LLE-HPLC-PDA-MS/MS in Drug Metabolism Studies: Identification of New Nabumetone Metabolites
Authors: Nobilis Milan | Mikušek Jiří | Szotaková Barbora | Jirásko Robert | Holčapek Michal | Chamseddin Chamseddin | Jira Thomas | Kučera Radim | Kuneš Jiří | Pour Milan
Year: 2013
Type of publication: článek v odborném periodiku
Name of source: Journal of Pharmaceutical and Biomedical Analysis
Publisher name: Pergamon-Elsevier Science Ltd.
Place: Oxford
Page from-to: 164-172
Titles:
Language Name Abstract Keywords
cze Aplikace LLE-HPLC-PDA-MS/MS při studiu metabolismu léčiv: Identifikace nového metabolitu nabumetonu V publikaci je popsán nový metabolit 1. fázena léčiva nabumetonu. Identifikace byla provedena na základě interpretace analytických dat získaných z UHPLC/MS/MS nabumeton; UHPLC/MS/MS; metabolismus léčiv
eng Analytical Power of LLE-HPLC-PDA-MS/MS in Drug Metabolism Studies: Identification of New Nabumetone Metabolites Following oral administration, nabumetone is converted in the liver to 6-methoxy-2-naphthylacetic acid (6-MNA), the principal metabolite responsible for the NSAID effect. In this study, a new, as yet unreported phase 1 metabolite was discovered within the evaluation of nabumetone metabolism by human and rat liver microsomal fractions. Extracts from the biomatrices were subjected to chiral LLE-HPLC-PDA and achiral LLE-UHPLC-MS/MS analyses to elucidate the chemical structure of this metabolite. UHPLC-MS/MS experiments detected the presence of a structure corresponding to elemental composition C15H16O3, which was tentatively assigned as a hydroxylated nabumetone. Identical nabumetone and HO-nabumetone UV spectra obtained from the FDA detector ruled out the presence of the hydroxy group in the aromatic moiety of nabumetone. Hence, the most likely structure of the new metabolite was 4-(6-methoxy-2-naphthyl)-3-hydroxybutan-2-one (3-hydroxy nabumetone). To confirm this structure, the standard of this nabumetone metabolite was synthesized, its spectral (UV, CD, NMR, MS/MS) and retention properties on chiral and achiral chromatographic columns were evaluated and compared with those of the authentic nabumetone metabolite. To elucidate the subsequent biotransformation of 3-hydroxy nabumetone, the compound was used as a substrate in incubation with human and rat liver microsomal fraction. A number of 3-hydroxy nabumetone metabolites (products of conjugation with glucuronic acid, O-desmethylation, carbonyl reduction and their combination) were discovered in the extracts from the incubated microsomes using LLE-HPLC-PDA-MS/MS experiments. On the other hand, when 3-hydroxy nabumetone was incubated with isolated rat hepatocytes, 6-MNA was detected as the principal metabolite of 3-hydroxy nabumetone. Hence, 3-hydroxy nabumetone could be the missing link in nabumetone biotransformation to 6-MNA (i.e. nabumetone -> 3-hydroxy nabumetone -> 6-MNA). Nabumetone biotransformation; 3-Hydroxy nabumetone; Synthesis; Chiral and achiral; LLE-HPLC-PDA-ESI-MS/MS; Microsomal fraction; Isolated hepatocytes

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