Kim Eun-Joo, Seo Joung-Wook, Hwang Ji-Yoon, Han Sang-Seop
Department of Pharmacology and National Research Laboratory, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Yuseong, Daejeon, Korea.
Drug Chem Toxicol. 2005;28(2):177-86. doi: 10.1081/dct-52525.
Sildenafil, a potent PDE5 inhibitor, is widely prescribed as a treatment of erectile dysfunction. Itraconazole is an inhibitor of CYP3A4, a metabolic enzyme of sildenafil. In the current study, we investigated the effects of single treatment with sildenafil and combined treatment with sildenafil and itraconazole on blood pressure, heart rate, and QT interval in conscious beagle dogs. After a transmitter was implanted to beagle dogs for conscious state experiments, a single oral dose of sildenafil was administered to the beagle dogs at dose levels of 3, 15, and 30 mg/kg. Blood pressure, heart rate, and lead II ECG were measured prior to dosing and at 0.5, 1, 2, 4, 6, and 24 h postdosing. In the study of combined treatment with sildenafil and itraconazole, the 100 mg/kg dose of itraconazole was orally administered 1 h prior to oral administration of sildenafil. No changes in blood pressure were observed at any doses in animals receiving either single treatment with sildenafil or combined treatment with sildenafil and itraconazole. Increased heart rate from 0.5 h to 6 h postdosing and decreased QT interval were observed in animals receiving single treatment with sildenafil at 15 or 30 mg/kg. When 30 mg/kg of sildenafil was coadministered with 100 mg/kg of itraconazole, drug-related effects such as increased heart rate and decreased QT interval were significantly enhanced as compared to sildenafil-alone administration at 6 h postadministration. These results demonstrated that increased heart rate and decreased QT interval, the adverse effects of sildenafil, were enhanced and prolonged when sildenafil was coadministered with itraconazole. Therefore, caution should be taken when sildenafil is coadministered with itraconazole, a CYP3A4 inhibitor, or when administered to elderly patients or patients with hepatic or renal impairment who cannot metabolize and excrete sildenafil normally.
西地那非是一种强效磷酸二酯酶5（PDE5）抑制剂，被广泛用于治疗勃起功能障碍。伊曲康唑是西地那非的代谢酶CYP3A4的抑制剂。在本研究中，我们调查了西地那非单药治疗以及西地那非与伊曲康唑联合治疗对清醒比格犬血压、心率和QT间期的影响。在将传感器植入比格犬以进行清醒状态实验后，分别以3、15和30mg/kg的剂量水平给比格犬口服单剂量西地那非。在给药前以及给药后0.5、1、2、4、6和24小时测量血压、心率和II导联心电图。在西地那非与伊曲康唑联合治疗的研究中，在口服西地那非前1小时口服100mg/kg剂量的伊曲康唑。接受西地那非单药治疗或西地那非与伊曲康唑联合治疗的动物在任何剂量下均未观察到血压变化。接受15或30mg/kg西地那非单药治疗的动物在给药后0.5小时至6小时心率增加，QT间期缩短。当30mg/kg西地那非与100mg/kg伊曲康唑合用时，与单独给予西地那非相比，给药后6小时与药物相关的心率增加和QT间期缩短等效应显著增强。这些结果表明，西地那非与伊曲康唑合用时，西地那非的不良反应心率增加和QT间期缩短会增强并延长。因此，当西地那非与CYP3A4抑制剂伊曲康唑合用时，或给不能正常代谢和排泄西地那非的老年患者或肝肾功能不全患者使用时，应谨慎用药。
