TY - JOUR
T1 - NMR-based pharmacometabonomic analysis of normal rat urine and faeces in response to (±)-venlafaxine treatment
AU - Serrano-Contreras, José I.
AU - García-Pérez, Isabel
AU - Meléndez-Camargo, María E.
AU - Zepeda-Vallejo, Luis G.
N1 - Publisher Copyright:
© 2016 Elsevier B.V.
PY - 2016/5/10
Y1 - 2016/5/10
N2 - (±)-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.
AB - (±)-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.
KW - (±)-Venlafaxine
KW - Gut microbial co-metabolite
KW - Multiorgan axis
KW - Multivariate data analysis
KW - NMR-based pharmacometabonomics
KW - Xenometabolome
UR - http://www.scopus.com/inward/record.url?scp=84958212573&partnerID=8YFLogxK
U2 - 10.1016/j.jpba.2016.01.044
DO - 10.1016/j.jpba.2016.01.044
M3 - Artículo
C2 - 26895493
SN - 0731-7085
VL - 123
SP - 82
EP - 92
JO - Journal of Pharmaceutical and Biomedical Analysis
JF - Journal of Pharmaceutical and Biomedical Analysis
ER -