Practical application of guinea pig telemetry system for QT evaluation.
The purpose of this study was to evaluate a telemetry system for examining QT evaluation in the conscious free-moving guinea pig using 10 reference compounds whose effects on human QT interval are well established: 8 positive references (bepridil, terfenadine, cisapride, haloperidol, pimozide, quinidine, E-4031 and thioridazine), and 2 negative references (propranolol and nifedipine). Pharmacokinetic experiments were also performed for the 8 positive references. Telemetry transmitters were implanted subcutaneously in male Hartley guinea pigs, and the RR and QT intervals were measured. All 8 positive references prolonged QTc (QTc = k x QT/RR(1/2)) 10% or more during the 60 min observation period. When the values of the QTc changes were plotted against the serum concentrations, the resulting curves exhibited an anticlockwise hysteresis loop for all 8 references. In guinea pigs treated with haloperidol, changes of the T-wave shape from positive to flat were observed. The 2 negative references did not prolong the QTc. These findings suggest that the present telemetry guinea pig model is useful for QT evaluation in the early stages of drug development, because of the small body size of guinea pigs and their action potential configuration, which is similar to that of humans.
Shiotani
Motohiro
M
Worldwide Safety Sciences, Pfizer Global Research and Development, Nagoya Laboratories, Pfizer Japan Inc., Aichi.
Harada
Takuma
T
Abe
Junko
J
Sawada
Yasufusa
Y
Hashimoto
Keitaro
K
Hamada
Yoshimasa
Y
Horii
Ikuo
I
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D015764:Bepridil / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D020117:Cisapride / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004562:Electrocardiography / Q000379:methods*; D006168:Guinea Pigs; D006220:Haloperidol / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D006321:Heart / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D006801:Humans; D007275:Injections, Intravenous; D008133:Long QT Syndrome / Q000139:chemically induced / Q000175:diagnosis / Q000503:physiopathology*; D008297:Male; D009543:Nifedipine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D010868:Pimozide / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D010880:Piperidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D011802:Quinidine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D013686:Telemetry / Q000379:methods*; D016593:Terfenadine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D013881:Thioridazine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics
D000889:Anti-Arrhythmia Agents; D014150:Antipsychotic Agents; D010880:Piperidines; D011725:Pyridines; C063968:E 4031; D010868:Pimozide; D015764:Bepridil; D016593:Terfenadine; D009543:Nifedipine; D011802:Quinidine; D006220:Haloperidol; D013881:Thioridazine; D020117:Cisapride