title: Characterizing novel metabolic pathways of melatonin receptor agonist agomelatine using metabolomic approaches.
abstract: Agomelatine (AGM), an analog of melatonin, is a potential agonist at melatonin receptors 1/2 and a selective antagonist at 5-hydroxytryptamine 2C receptors. AGM is widely used for the treatment of major depressive episodes in adults. However, multiple adverse effects associated with AGM have been reported in clinical practice. It is little known about AGM metabolism in vitro and in vivo, although metabolism plays a pivotal role in its efficacy and safety. To elucidate metabolic pathways of AGM, we systemically investigated AGM metabolism and its bioactivation in human liver microsomes (HLM) and mice using metabolomic approaches. We identified thirty-eight AGM metabolites and adducts, among which thirty-two are novel. In HLM, we uncovered five GSH-trapped adducts and two semicarbazide-trapped aldehydes. Moreover, we characterized three N-acetyl cysteine conjugated-AGM adducts in mouse urine and feces, which were formed from the degradation of AGM_GSH adducts. Using recombinant CYP450 isoenzymes and chemical inhibitors, we demonstrated that CYP1A2 and CYP3A4 are primary enzymes contributing to the formation of AGM_GSH adducts and AGM_hydrazones. This study provided a global view of AGM metabolism and identified the novel pathways of AGM bioactivation, which could be utilized for further understanding the mechanism of adverse effects related to AGM and possible drug-drug interactions.
authors.affiliation: Department of Molecular and Cellular Biology, Alkek Center for Molecular Discovery, Advanced Technology Core, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Key Lab for Basic Pharmacology of Ministry of Education, Zunyi Medical College, Zunyi, Guizhou 563000, China.
authors.forename: Yuan-Fu
authors.initials: YF
authors.lastname: Lu
authors.affiliation: USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Xinfu
authors.initials: X
authors.lastname: Guan
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA; Graduate Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Mingkun
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Biology, Alkek Center for Molecular Discovery, Advanced Technology Core, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: fl3@bcm.edu.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
mesh_terms: D000081:Acetamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000652:urine*; D000818:Animals; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005243:Feces / Q000737:chemistry; D005786:Gene Expression Regulation; D005978:Glutathione / Q000737:chemistry; D006801:Humans; D006993:Hypnotics and Sedatives / Q000737:chemistry / Q000493:pharmacokinetics / Q000652:urine*; D007527:Isoenzymes / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000235:genetics; D055432:Metabolomics; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D044094:Receptors, Melatonin / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D012663:Semicarbazides / Q000737:chemistry; D015398:Signal Transduction; D009281:Naphthalenes
chemical_list: D000081:Acetamides; D003577:Cytochrome P-450 Enzyme System; D005978:Glutathione; D006993:Hypnotics and Sedatives; D007527:Isoenzymes; D044094:Receptors, Melatonin; D012663:Semicarbazides; C084711:agomelatine; D009281:Naphthalenes; C010059:carbamylhydrazine
keywords: Agomelatine; Melatonin-receptor; Metabolism; Metabolomics; Reactive metabolites