Iloperidone (Fanapt^庐), a novel atypical antipsychotic, is a potent HERG blocker and delays cardiac ventricular repolarization at clinically relevant concentration

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• 作者：Patrick Vigneault^a ; ^b ; ^{patrick.vigneault@criucpq.ulaval.ca} ; Sylvie Pilote^b ; ^{sylvie.pilote@criucpq.ulaval.ca} ; Dany Patoine^b ; ^{dany.patoine@criucpq.ulaval.ca} ; Chantale Simard^a ; ^b ; ^{chantale.simard@pha.ulaval.ca} ; Benoit Drolet^a ; ^b ; ^{benoit.drolet@pha.ulaval.ca}
• 关键词：Iloperidone ; Antipsychotic ; HERG blocker ; Cardiac ventricular repolarization
• 刊名：Pharmacological Research
• 出版年：2012
• 期刊代码：54_10436618
• 类别：pha
• 出版时间：July, 2012
• 卷：66
• 期：1
• 页码：60-65
• 文件大小：579 K

摘要

QT interval prolongation on the electrocardiogram (ECG) has extensively been reported with iloperidone, a novel antipsychotic drug. The objective of the present study was to evaluate the effects of iloperidone on cardiac ventricular repolarization at three different levels; in vitro, ex vivo and in vivo. (1) In vitro level: whole-cell patch-clamp experiments were performed on HERG-transfected HEK293 cells exposed to iloperidone 0.01-1 渭mol/L (n = 35 cells, total) to assess drug effect on HERG current. (2) Ex vivo level: Langendorff retroperfusion experiments were performed on isolated hearts from male Hartley guinea pigs (n = 7) exposed to iloperidone 100 nmol/L with/without chromanol 293B 10 渭mol/L to assess drug-induced prolongation of monophasic action potential duration measured at 90%repolarization (MAPD₉₀). (3) In vivo level: ECG recordings using wireless cardiac telemetry were performed in guinea pigs (n = 5) implanted with radio transmitters and treated with a single oral gavage dose of iloperidone 3 mg/kg. (1) Patch-clamp experiments revealed an estimated IC50 for iloperidone on HERG current of 161 卤 20 nmol/L. (2) While pacing the hearts at stimulation cycle lengths of 200 or 250 ms, or during natural sinus rhythm (no external pacing), iloperidone 100 nmol/L prolonged MAPD₉₀ by respectively 9.2 卤 0.9, 11.2 卤 1.6 and 21.4 卤 2.3 ms. After adding chromanol 293B, MAPD₉₀ was further prolonged by 7.3 卤 3.3, 11.5 卤 2.3 and 29.2 卤 6.7 ms, respectively. (3) Iloperidone 3 mg/kg p.o. caused a maximal 42.7 卤 10.2 ms prolongation of corrected QT interval (QTc_F), 40 min after administration. Iloperidone prolongs the QT interval, the cardiac action potentials and is a potent HERG blocker. Patients are at increased risk of cardiac proarrhythmia during iloperidone treatment, as this drug possesses significant cardiac repolarization-delaying properties at clinically relevant concentration.