title: Myocardium distribution of sertindole and its metabolite dehydrosertindole in guinea-pigs.
abstract: Sertindole, like other atypical antipsychotics, has been shown to increase the action potential duration and QT interval in a concentration dependent manner, in in vitro electrophysiological studies. However, this does not always translate into increased duration of the QT interval, increased risk of torsade de pointes or sudden death in clinical practice. The reasons for these apparent discrepancies are unclear and many studies have underscored the importance of the interpretation of in vitro electrophysiological data in the context of other pharmacodynamic (e.g. cardiac ion channels target, receptor affinity) and pharmacokinetic parameters (total plasma drug concentration and drug distribution). To address the possible relevance of the concentrations used in experimental studies, the myocardium distribution of sertindole and its metabolite was determined after single and repeated intraperitoneal administration to guinea-pigs. The data suggest that the plasma concentration appears to predict the concentration in the myocardium and that the myocardium concentrations of sertindole are 3.1 times higher than plasma concentrations. Using these data, the relevance of in vitro electrophysiological studies to clinical plasma concentrations has been appraised.
authors.affiliation: Department of Clinical Pharmacology and Toxicology, INSERM U657, IFR 99, Université Victor Segalen, 33076 Bordeaux Cedex, France. Mireille.Canal@pharmaco.u-bordeaux2.fr
authors.forename: Mireille
authors.initials: M
authors.lastname: Canal-Raffin
authors.forename: Karine
authors.initials: K
authors.lastname: Titier
authors.forename: Evelyne
authors.initials: E
authors.lastname: Déridet
authors.forename: Béatrice
authors.initials: B
authors.lastname: Martinez
authors.forename: Abdelilah
authors.initials: A
authors.lastname: Abouelfath
authors.forename: Alain
authors.initials: A
authors.lastname: Miras
authors.forename: Sophie
authors.initials: S
authors.lastname: Gromb
authors.forename: Mathieu
authors.initials: M
authors.lastname: Molimard
authors.forename: Nicholas
authors.initials: N
authors.lastname: Moore
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006168:Guinea Pigs; D007093:Imidazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007211:Indoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D009206:Myocardium / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; D007093:Imidazoles; D007211:Indoles; C066304:sertindole