Faculté de Pharmacie, Université Laval, Québec, Canada.
J Cardiovasc Pharmacol. 2011 Jun;57(6):690-5. doi: 10.1097/FJC.0b013e318217d941.
Paliperidone (9-hydroxyrisperidone) is a second-generation antipsychotic. As observed with risperidone, QT interval prolongation was reported with paliperidone.
The aim was to evaluate the effects of paliperidone on cardiac ventricular repolarization.
(1) Patch-clamp experiments: Human ether-a-go-go-related gene (HERG)- or KCNQ1 + KCNE1-transfected cells were exposed to 0.1-100 μmol/L paliperidone (N = 39 cells, total) to assess the drug effect on HERG and KCNQ1 + KCNE1 currents. (2) Langendorff perfusion experiments: Hearts isolated from male Hartley guinea pigs (N = 9) were exposed to 0.1 μmol/L paliperidone to assess drug-induced prolongation of monophasic action potential duration measured at 90% repolarization. (3) In vivo cardiac telemetry experiments: Guinea pigs (N = 8) implanted with transmitters were injected a single intraperitoneal dose of 1 mg/kg of paliperidone, and 24-hour electrocardiogram recordings were made.
(1) The estimated concentration at which 50% of the maximal inhibitory effect is observed (IC(50)) for paliperidone on HERG current was 0.5276 μmol/L. In contrast, 1 μmol/L paliperidone had hardly any effect on KCNQ1 + KCNE1 current (4.0 ± 1.6% inhibition, N = 5 cells). (2) While pacing the hearts at cycle lengths of 150, 200, or 250 milliseconds, 0.1 μmol/L paliperidone prolonged monophasic action potential duration measured at 90% repolarization by, respectively, 6.1 ± 3.1, 9.8 ± 2.7, and 12.8 ± 2.7 milliseconds. (3) Paliperidone (1 mg/kg) intraperitoneal caused a maximal 15.7 ± 5.3-millisecond prolongation of QTc.
Paliperidone prolongs the QT interval by blocking HERG current at clinically relevant concentrations and is potentially unsafe.
帕利哌酮（9-羟基利培酮）是一种第二代抗精神病药物。与利培酮一样，帕利哌酮也会导致 QT 间期延长。
评估帕利哌酮对心室复极的影响。
（1）膜片钳实验：将人 ether-a-go-go-related gene（HERG）或 KCNQ1+KCNE1 转染细胞暴露于 0.1-100μmol/L 的帕利哌酮（N=39 个细胞，总数），以评估药物对 HERG 和 KCNQ1+KCNE1 电流的影响。（2）Langendorff 灌注实验：将雄性 Hartley 豚鼠心脏（N=9）分离出来，暴露于 0.1μmol/L 的帕利哌酮，以评估药物诱导的复极 90%时单相动作电位时程的延长。（3）体内心脏遥测实验：将植入发射器的豚鼠（N=8）单次腹腔注射 1mg/kg 的帕利哌酮，进行 24 小时心电图记录。
（1）帕利哌酮对 HERG 电流的 50%最大抑制作用的估计浓度（IC50）为 0.5276μmol/L。相比之下，1μmol/L 的帕利哌酮对 KCNQ1+KCNE1 电流几乎没有影响（抑制 4.0±1.6%，N=5 个细胞）。（2）当以 150、200 或 250 毫秒的心动周期起搏心脏时，0.1μmol/L 的帕利哌酮分别使复极 90%时的单相动作电位时程延长 6.1±3.1、9.8±2.7 和 12.8±2.7 毫秒。（3）帕利哌酮（1mg/kg）腹腔注射可使 QTc 最大延长 15.7±5.3 毫秒。
帕利哌酮在临床相关浓度下通过阻断 HERG 电流延长 QT 间期，存在潜在的不安全因素。
