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Drug Metabolism and Disposition Fast Forward
First published on February 27, 2009; DOI: 10.1124/dmd.108.025817

0090-9556/09/3706-1157-1163$20.00
DMD 37:1157-1163, 2009

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Fenofibrate Metabolism in the Cynomolgus Monkey using Ultraperformance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry-Based MetabolomicsFormula

Aiming Liu, Andrew D. Patterson, Zongtao Yang, Xinying Zhang, Wei Liu, Fayang Qiu, He Sun, Kristopher W. Krausz, Jeffrey R. Idle, Frank J. Gonzalez, and Renke Dai

Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China (A.L., Z.Y., X.Z., W.L., F.Q., H.S., R.D.); 1st Faculty of Medicine, Charles University, Prague, Czech Republic (J.R.I.); and National Cancer Institute, National Institutes of Health, Bethesda, Maryland (A.D.P., K.W.K., F.J.G.)

Fenofibrate, widely used for the treatment of dyslipidemia, activates the nuclear receptor, peroxisome proliferator-activated receptor {alpha}. 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.

Address correspondence to: Dr. Renke Dai, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510663, China. E-mail: dai_renke{at}gibh.ac.cn






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