Cardiohemodynamic and Electrophysiological Effects of Anti-influenza Drug Oseltamivir In Vivo and In Vitro Ken Kitahara • Yuji Nakamura • Yayoi Tsuneoka • Satomi Adachi-Akahane • Hikaru Tanaka • Hiroshi Yamazaki • Akira Takahara • Junichi Yamazaki • Takanori Ikeda • Atsushi Sugiyama Published online: 19 February 2013 Ó Springer Science+Business Media New York 2013 Abstract Electropharmacological effects of oseltamivir were studied in comparison with pilsicainide using halo- thane-anesthetized dogs (n= 4) and isolated left atrium of guinea pigs (n= 5). Oseltamivir (0.3, 3 and 30 mg/kg, i.v.) or pilsicainide (1 and 3 mg/kg, i.v.) was additionally administered to the dogs. The low dose of oseltamivir pro- vided clinically relevant plasma concentrations with C max of 4 lM. The low and middle doses of oseltamivir increased cardiac output, whereas the middle dose increased blood pressure and delayed intra-atrial conduction and ventricular repolarization. The high dose of oseltamivir exerted negative chronotropic, inotropic and hypotensive effects, while it delayed intra-atrial, atrioventricular nodal and intra-ven- tricular conduction and ventricular repolarization. Use- dependent delay of ventricular repolarization was observed after oseltamivir, whereas reverse use-dependent prolonga- tion was induced by pilsicainide. Moreover, oseltamivir more selectively suppressed intra-atrial conduction than intra-ventricular conduction, which was less selective for pilsicainide. Action potential assay using isolated atrium indicated that oseltamivir (10 lM) decreased V max more than pilsicainide (10 lM) and that oseltamivir (10–100 lM) prolonged action potential duration, which was not induced by pilsicainide (1–10 lM). Thus, oseltamivir in clinically relevant to its 10 times higher doses is relatively safe, whereas 10–100 times higher doses possess unique electro- physiological profile. Keywords Oseltamivir Á Pilsicainide Á QT Á Torsades de pointes Á Cardiac death Introduction Oseltamivir is a potent and selective neuraminidase enzyme inhibitor and is one of the most effective drugs against the novel influenza virus infection, which has gained worldwide attention in view of the Influenza A (H1N1) pandemic, namely swine flu [1]. A previous large study of insurance records in the early 2000s showed no evidence of an increased risk of cardiac, neuropsychiatric or respiratory events for patients receiving oseltamivir compared with those who did not [2]. On the other hand, it was reported recently that 2 cases, patients who had tol- erated long-term sotalol, developed marked QT-interval prolongation and required resuscitation from torsades de K. Kitahara Á Y. Nakamura Á S. Adachi-Akahane Á A. Sugiyama (&) Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-Nishi, Ota-ku, Tokyo 143-8540, Japan e-mail: atsushi.sugiyama@med.toho-u.ac.jp K. Kitahara Á J. Yamazaki Á T. Ikeda Division of Cardiovascular Medicine, Department of Internal Medicine, Faculty of Medicine, Toho University, 6-11-1 Omori-Nishi, Ota-ku, Tokyo 143-8541, Japan Y. Tsuneoka Á H. Tanaka Á A. Takahara Department of Pharmacology, Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan H. Yamazaki Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, 3-3165 Higashi-tamagawa Gakuen, Machida, Tokyo 194-8543, Japan A. Takahara Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan 123 Cardiovasc Toxicol (2013) 13:234–243 DOI 10.1007/s12012-013-9202-6