Abstract
Fenofibrate, widely used for the treatment of dyslipidemia, activates the nuclear receptor, peroxisome proliferator-activated receptor α. However, liver toxicity, including liver cancer, occurs in rodents treated with fibrate drugs. Marked species differences occur in response to fibrate drugs, especially between rodents and humans, the latter of which are resistant to fibrate-induced cancer. Fenofibrate metabolism, which also shows species differences, has not been fully determined in humans and surrogate primates. In the present study, the metabolism of fenofibrate was investigated in cynomolgus monkeys by ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOFMS)-based metabolomics. Urine samples were collected before and after oral doses of fenofibrate. The samples were analyzed in both positive-ion and negative-ion modes by UPLC-QTOFMS, and after data deconvolution, the resulting data matrices were subjected to multivariate data analysis. Pattern recognition was performed on the retention time, mass/charge ratio, and other metabolite-related variables. Synthesized or purchased authentic compounds were used for metabolite identification and structure elucidation by liquid chromatographytandem mass spectrometry. Several metabolites were identified, including fenofibric acid, reduced fenofibric acid, fenofibric acid ester glucuronide, reduced fenofibric acid ester glucuronide, and compound X. Another two metabolites (compound B and compound AR), not previously reported in other species, were characterized in cynomolgus monkeys. More importantly, previously unknown metabolites, fenofibric acid taurine conjugate and reduced fenofibric acid taurine conjugate were identified, revealing a previously unrecognized conjugation pathway for fenofibrate.
Footnotes
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This work was supported in part by the National Institutes of Health National Cancer Institute [Grant Z01 BC005562-20] (Intramural Research Program); the National High-tech R&D Program [Grant 2006AA02Z339]; the Guangzhou Science and Technology Bureau [Grants 2006Z1-E4031, 2006P067]; and the Guangzhou Development District [Grant 2006Ss-P067].
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.108.025817.
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ABBREVIATIONS: PPARα, peroxisome proliferator-activated receptor α; NHP, nonhuman-primate; FA, fenofibric acid; RFA, reduced fenofibric acid; FAEG, fenofibric acid ester glucuronide; RFAEG, reduced fenofibric acid ester glucuronide; MDA, multivariate data analysis; UPLC, ultraperformance liquid chromatography; QTOFMS, quadrupole time-of-flight mass spectrometry; PLS-DA, projection to latent structures discriminant analysis; FAT, fenofibric acid taurine conjugate; RFAT, reduced fenofibric acid taurine conjugate; compound A, 4-chloro-4′-hydroxybenzophenone; compound AR, compound A reduced; compound X, 2-[4-(4-chloro-benzoyl)-phenoxy]-2-methylpropionic acid methyl ester; compound B, 4-chloro-4′-isopropoxybenzophenone; TLC, thin-layer chromatography; MS/MS, tandem mass spectrometry; MRM, multiple reaction monitoring; LC, liquid chromatography; MS, mass spectrometry.
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↵ The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
- Received December 2, 2008.
- Accepted February 26, 2009.
- U.S. Government work not protected by U.S. copyright.
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