title: Fenofibrate metabolism in the cynomolgus monkey using ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry-based metabolomics.
abstract: 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.
authors.affiliation: Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510663, China.
authors.forename: Aiming
authors.initials: A
authors.lastname: Liu
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Patterson
authors.forename: Zongtao
authors.initials: Z
authors.lastname: Yang
authors.forename: Xinying
authors.initials: X
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Fayang
authors.initials: F
authors.lastname: Qiu
authors.forename: He
authors.initials: H
authors.lastname: Sun
authors.forename: Kristopher W
authors.initials: KW
authors.lastname: Krausz
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Idle
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Renke
authors.initials: R
authors.lastname: Dai
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D004285:Dogs; D011345:Fenofibrate / Q000737:chemistry / Q000378:metabolism*; D006168:Guinea Pigs; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008252:Macaca fascicularis / Q000378:metabolism*; D013058:Mass Spectrometry; D055432:Metabolomics; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization; D013552:Swine; D053719:Tandem Mass Spectrometry
chemical_list: D000960:Hypolipidemic Agents; D011345:Fenofibrate