title: Reversible cardiac dysfunction after venlafaxine overdose and possible influence of genotype and metabolism.
abstract: Acute poisoning by large venlafaxine (VEN) overdoses may result in serious cardiac events like acute left ventricular dysfunction or even fatalities. In humans, venlafaxine is biotransformed for the most part by CYP2D6 and CYP2C19 isoenzymes to its major metabolite O-desmethylvenlafaxine (ODV), and in parallel to N-desmethylvenlafaxine (NDV) and N,O-didesmethylvenlafaxine (NODV) by several CYP isoenzymes, mainly including CYP3A4 and CYP2C19. The ODV concentrations must be taken into consideration along with those of VEN when relating blood concentrations to clinical effects. Herein we describe a case of reversible cardiac dysfunction following VEN self-poisoning. The peak ODV concentration (46,094ng/mL) was observed 20h post-ingestion, being one of the highest ever associated with survival. The calculated elimination half-life was 10h for VEN and 22h for ODV, and the calculated ODV/VEN metabolic ratio 12.9. Genotyping confirmed the patient to have an extensive metabolizer phenotype for CYP2D6, and an ultra-rapid metabolizer phenotype for CYP2C19. We suspect cardiotoxicity was related to sustained ODV exposure despite extensive VEN metabolism, and therefore suggest that ODV metabolism saturation may occur following large VEN overdoses.
authors.affiliation: Department of Intensive Care, Cliniques St-Luc, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Diego
authors.initials: D
authors.lastname: Castanares-Zapatero
authors.affiliation: Department of Clinical Pharmacy, Cliniques St-Luc, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Gillard
authors.affiliation: Louvain Centre for Toxicology and Applied Pharmacology, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Capron
authors.affiliation: Louvain Centre for Toxicology and Applied Pharmacology, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Vincent
authors.initials: V
authors.lastname: Haufroid
authors.affiliation: Department of Intensive Care, Cliniques St-Luc, Université catholique de Louvain, Brussels, Belgium; Louvain Centre for Toxicology and Applied Pharmacology, Université catholique de Louvain, Brussels, Belgium. Electronic address: philippe.hantson@uclouvain.be.
authors.forename: Philippe
authors.initials: P
authors.lastname: Hantson
mesh_terms: D018687:Antidepressive Agents, Second-Generation / Q000009:adverse effects*; D066126:Cardiotoxicity / Q000209:etiology*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D003863:Depression / Q000188:drug therapy; D062787:Drug Overdose; D005260:Female; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D013406:Suicide, Attempted; D000069470:Venlafaxine Hydrochloride / Q000009:adverse effects*
chemical_list: D018687:Antidepressive Agents, Second-Generation; D000069470:Venlafaxine Hydrochloride; D019389:Cytochrome P-450 CYP2D6
keywords: Cardiotoxicity; Genotyping; Metabolism; O-desmethylvenlafaxine; Overdose; Venlafaxine