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

Abstract

ABSTRACT:Fenofibrate, widely used for the treatment of dyslipidemia, activates the nuclear receptor, peroxisome proliferator-activated receptor ␣. 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.

Development of a sensitive liquid chromatography/tandem mass spectrometry method for the determination of fenofibric acid in rat plasma

“…Fenofibric acid, affecting lipid metabolism, is mainly mediated through the activation of peroxisome proliferator‐activated receptor. It is also able to reduce total cholesterol, low‐density‐lipoprotein cholesterol, apolipoprotien B, total triglycerides and triglyceride‐rich lipoprotein (Martin et al ., ; Liu et al ., ). Fenofibrate can be administered once daily as the elimination half‐life of fenofibric acid is about 20 h (Straka et al ., ).…”

Towards Polypharmacokinetics: Pharmacokinetics of Multicomponent Drugs and Herbal Medicines Using a Metabolomics Approach

“…To date, metabolomics techniques have been employed in metabolism studies of dozens of single xenobiotics with diverse chemical structures (Table 1), including GSK-X [29], citalopram [30], aminoflavone [34], arecoline/arecaidine [35], PhIP [36], arecoline 1-oxide [37], ferulic and sinapic acids [38], acetaminophen [39–42], dextromethorphan [43], melatonin [44, 45], vitamin E [46], fenofibrate [47, 48], tolcapone [49], cyclophosphamide/ifosfamide [50], tipranavir [51], nefazodone [52], valproic acid [53], ritonavir [54], pulegone/clozapine [42], thioTEPA [55], isoliquiritigenin [56], ethanol [57], and procainamide [58]. Remarkably, majority of these studies were carried out in vivo .…”

Determination of Fenofibric Acid in Human Plasma by LC–MS/MS and LC–UV

“…FFA has long been determined in human body by many analytical methods involving various techniques of LC-UV [22-25] and LC-MS/MS [26][27][28][29]. But the analysis time was not less than 9 min by LC-UV [24], and 1.5 min by LC-MS/MS [30], at the most sensitive wide dynamic range of 0.05-10 µg mL −1 [25].…”