865 Severe acute cardiomyopathy associated with venlafaxine overdose and possible role of CYP2D6 and CYP2C19 polymorphisms MARCO VINETTI 1 , VINCENT HAUFROID 2 , ARNAUD CAPRON 2 , JEAN-FRANÇOIS CLASSEN 2 , SEBASTIEN MARCHANDISE 3 , and PHILIPPE HANTSON 1 1 Cliniques St-Luc, Université catholique de Louvain, Intensive Care, Avenue Hippocrate 10, Brussels, 1200 Belgium 2 Université catholique de Louvain, Louvain Centre for Toxicology and Applied Pharmacology, Avenue Hippocrate 10, Brussels, 1200 Belgium 3 Cliniques St-Luc, Cardiology, Avenue Hippocrate 10, Brussels, 1200 Belgium Introduction. Venlafaxine (VEN) is a serotonin-norepinephrine-dopamine reuptake inhibitor that causes usually a mild cardiotoxicity when ingested in overdose. We report a patient who developed acute heart failure following overdose. As the toxicokinetic data suggested a prolonged metabolism, genetic polymorphisms for cytochrome P450 isoenzymes CYP2D6 and CYP2C19 were also investigated. Case report. A 34-year-old woman was admitted to the hospital 10 hours after the ingestion of an 11.25 g overdose of VEN. She was comatose and suffered two self-limited seizures. The electrocardiogram showed diffuse ST segment depression, but normal QRS and QTc duration. The plasma levels on admission were 18 015 and 3 846 ng/ml for VEN and the metabolite O-desmethylvenlafaxine (ODV), respectively. The patient developed severe cardiodepression. The left ventricular shortening fraction was only 9% on echocardiography. The patient was oliguric and required continuous venovenous hemofiltration. The administration of milrinone was required for 12 days, and norepinephrine for 10 days. Left ventricular function recovered. The calculated elimination half-life was 30.8 and 72.2 hours for VEN and ODV, respectively. The patient genotype was CYP2D6*1/*5, the *5 allele corresponding to a complete deletion of CYP2D6 gene. Conclusions. Severe and sustained cardiotoxicity following VEN overdose may be related to the amount ingested, as well as to the genetic polymorphism for CYP2D6 leading to a delayed elimination of active metabolite. Keywords Heart; Cardiac support; CNS/ Psychological Introduction Venlafaxine(VEN) is a serotonin-norepinephrine-dopamine reuptake inhibitor (SNRI) that rarely causes life-threatening cardiac manifestations following overdose. We report here a case of severe and sustained cardiotoxicity after an overdose of 11.25 g in a 34-year-old patient without previous cardiac disease. VEN is extensively metabolized by the liver mainly through the cytochrome P450-2D6 and -2C19 isoenzymes (CYP2D6 and CYP2C19) to form its major pharmacologi- cally active metabolite, O-desmethylvenlafaxine (ODV); a minor metabolite, N-desmethylvenlafaxine, is also formed by CYP3A4 and possibly CYP2C19. We investigated in this case the possible role of CYP2D6 and CYP2C19 genetic polymorphism in VEN/ODV toxicokinetics and toxicodynamics. Case report A 34-year-old depressive woman (65 kg weight) was admit- ted to the Emergency Department (ED) 10 hours after a drug overdose. According to the relatives, she could have ingested a maximal dose of 20 g of acetaminophen, 7.5 g of extended- release VEN and 3.75 g of immediate-release VEN. She had been found unresponsive by the first medical rescuers, with a Glasgow Coma Score (GCS) of 8/15. As cough and gag reflexes were preserved, intubation was not performed at the scene. Vital signs on admission in the ED were as follows: arterial blood pressure 116/53 mmHg, heart rate 130/minute, temperature 37.3°C. Her GCS was still 8/15, and the pupils were dilated bilaterally. She suffered two self-limited gener- alized seizures soon after admission and orotracheal intuba- tion was subsequently performed. The brain computerized tomography was normal. The admission 12-lead ECG performed after seizures episode (Fig. 1) showed a sinus rhythm 107/min, QRS duration 80 msec, QTc 403 msec, and ST segment depression in the anterior-and inferior- leads consistent with subendocardial ischemia. The com- prehensive blood toxicological screen (ultra-performance liquid chromatography method with diode array detection) Clinical Toxicology (2011), 49, 865–869 Copyright © 2011 Informa Healthcare USA, Inc. ISSN: 1556-3650 print / 1556-9519 online DOI: 10.3109/15563650.2011.626421 BRIEF COMMUNICATION Received 27 April 2011; accepted 16 September 2011. Address correspondence to Prof. Marco Vinetti, Cliniques St Luc, Intensive Care, Avenue Hippocrate 10, Brussels, 1200 Belgium. E-mail: philippe.hantson@uclouvain.be