title: NMR-based metabonomic analysis of normal rat urine and faeces in response to (±)-venlafaxine treatment.
abstract: (±)-Venlafaxine, a bicyclic antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNRI) class, is prescribed for the treatment of depression and anxiety disorders. As is the case with other antidepressants, its precise mechanisms of action are still unknown. Pharmacometabonomic approaches allow for the detection of diverse metabolites, unlike classic methods for analysing drug interaction based on single metabolites and linear pathways. This provides a global view of the state of homeostasis during treatment and an insight into the mechanisms of action of a drug. Accordingly, the final outcome of treatment is characterised by the network of reactome pathways derived from the on-target and off-target effects of the drug. Regarding antidepressants, the drug network may be located in the gut-microbiome-brain-liver-kidney-immune-cardiovascular system axis (GMBLKICA), implying that neurotransmitters participate as signalling molecules in bidirectional communication. If their bioavailability is increased, this communication and the state of homeostasis may be disrupted. With a pharmacometabonomic approach using NMR in combination with different chemometric methods, a determination was made of subtle changes in the metabolic profile (metabotype) of urine and faeces in normal Wistar rats following a single administration of pharmacological doses of (±)-venlafaxine hydrochloride. Based on the drug-response metabotypes observed, (±)-venlafaxine had effects on gut microbial co-metabolites and osmolytes. Hence, it can be hypothesized that bidirectional communication in the multiorgan axis was perturbed by this drug, and very likely by its active metabolite, (±)-desvenlafaxine. This disrupted signalling could be related not only to therapeutic and adverse effects, but also to the lag period in treatment response.
authors.affiliation: Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala s/n, Col. Santo Tomas C.P. 11340, Delegación Miguel Hidalgo, México, D.F., Mexico; Departamento de Farmacia, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Av. Wilfrido Massieu s/n, Esq. Manuel Stampa, Unidad Profesional Adolfo López Mateos, C.P. 07738, Delegación Gustavo A. Madero, México, D.F., Mexico.
authors.forename: José I
authors.initials: JI
authors.lastname: Serrano-Contreras
authors.affiliation: Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London SW7 2AZ, United Kingdom.
authors.forename: Isabel
authors.initials: I
authors.lastname: García-Pérez
authors.affiliation: Departamento de Farmacia, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Av. Wilfrido Massieu s/n, Esq. Manuel Stampa, Unidad Profesional Adolfo López Mateos, C.P. 07738, Delegación Gustavo A. Madero, México, D.F., Mexico.
authors.forename: María E
authors.initials: ME
authors.lastname: Meléndez-Camargo
authors.affiliation: Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala s/n, Col. Santo Tomas C.P. 11340, Delegación Miguel Hidalgo, México, D.F., Mexico. Electronic address: lzepeda@woodward.encb.ipn.mx.
authors.forename: Luis G
authors.initials: LG
authors.lastname: Zepeda-Vallejo
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000378:metabolism / Q000494:pharmacology / Q000652:urine; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003863:Depression / Q000188:drug therapy / Q000378:metabolism / Q000652:urine; D000069468:Desvenlafaxine Succinate / Q000378:metabolism / Q000652:urine; D005243:Feces / Q000737:chemistry*; D005260:Female; D008279:Magnetic Resonance Imaging / Q000379:methods; D055432:Metabolomics / Q000379:methods; D018377:Neurotransmitter Agents / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism / Q000494:pharmacology / Q000652:urine; D014556:Urine / Q000737:chemistry*; D000069470:Venlafaxine Hydrochloride / Q000378:metabolism* / Q000494:pharmacology / Q000652:urine
chemical_list: D000928:Antidepressive Agents; D000069468:Desvenlafaxine Succinate; D018377:Neurotransmitter Agents; D009638:Norepinephrine; D017367:Selective Serotonin Reuptake Inhibitors; D000069470:Venlafaxine Hydrochloride
keywords: (±)-Venlafaxine; Gut microbial co-metabolite; Multiorgan axis; Multivariate data analysis; NMR-based pharmacometabonomics; Xenometabolome