Famotidine does not induce long QT syndrome: experimental evidence from in vitro and in vivo test systems.
The effects of famotidine on the cardiac repolarization process were assessed using four different levels of test systems described in the draft stage guideline ICH S7B. A supratherapeutic concentration of famotidine (10(-5) M), which is >8 times higher than C(max) obtained after its therapeutic dose, neither inhibited human ether-a-go-go-related gene (HERG) K(+) current expressed in human embryonic kidney 293 (HEK293) cells nor affected any of the action potential parameters of guinea pig papillary muscles. Therapeutic (0.3 mg/kg, i.v.) to supratherapeutic doses (3-10 mg/kg, i.v.) of famotidine did not affect the repolarization process of the halothane-anesthetized canine model, while only supratherapeutic doses exerted the positive chronotropic, inotropic and dromotropic effects without affecting the mean blood pressure. Moreover, supratherapeutic doses of famotidine (1-10 mg/kg, i.v.) neither induced torsades de pointes nor prolonged QT interval in the canine chronic atrioventricular conduction block model. These results suggest that famotidine possesses no cardiovascular effects at a therapeutic dose, while it may exert cardiostimulatory actions after drug overdoses that might potentiate the proarrhythmic potential of co-administered cardiotonic agents by increasing the intracellular Ca(2+) concentration.
Sugiyama
Atsushi
A
Department of Pharmacology, University of Yamanashi Interdisciplinary Graduate School of Medicine and Engineering, Tamaho-cho, Nakakoma-gun, Yamanashi 409-3898, Japan. atsushis@res.yamanashi-med.ac.jp
Satoh
Yoshioki
Y
Takahara
Akira
A
Nakamura
Yuji
Y
Shimizu-Sasamata
Masao
M
Sato
Shuichi
S
Miyata
Keiji
K
Hashimoto
Keitaro
K
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D027682:Cation Transport Proteins; D002460:Cell Line; D004268:DNA-Binding Proteins; D004285:Dogs; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels; D015738:Famotidine / Q000009:adverse effects*; D006168:Guinea Pigs; D006327:Heart Block / Q000139:chemically induced / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000009:adverse effects*; D006801:Humans; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides / Q000494:pharmacology; D016593:Terfenadine / Q000494:pharmacology; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006634:Histamine H1 Antagonists; D006635:Histamine H2 Antagonists; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D015738:Famotidine; D016593:Terfenadine; C063533:dofetilide