Pharmacokinetic-pharmacodynamic analysis of the electrocardiographic effects of terfenadine and quinidine in rats.
In establishing a method of electrocardiographic (ECG) measurement for investigating drug-induced ECG changes, we examined the ECG effects and pharmacokinetics of terfenadine (TFN) and quinidine (QND) in rats. The time profiles of the plasma concentration and ECG parameters, such as the QT interval determined from limb lead II (QT-II) and the precordial chest lead (QT-V), heart rate and PR interval, were examined during constant intravenous infusion of TFN (5 or 15 mg/kg/h) or QND sulfate dihydrate (10 or 30 mg/kg/h). Both agents provided significant and concentration-dependent QT prolongation. The plasma concentrations (C10), where 10 ms of QT prolongation was observed, were 1.03 microM for TFN and 5.12 microM for QND, respectively. The calculated plasma unbound concentration of C10 (C10-f) was 10.3 nM for TFN and 3.82 microM for QND, which coincides with previously reported in vitro values of IC50 for potassium channels. The drug-induced QT prolongation was quantitatively reproduced in rats within the clinical concentration range. The usefulness of our methodology for the evaluation of arrhythmogenic hazards of the drugs was also demonstrated.
Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, Japan.
H
H
Ohtani
E
E
Hanada
K
K
Yamamoto
Y
Y
Sawada
T
T
Iga
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000503:physiopathology*; D004347:Drug Interactions; D004562:Electrocardiography / Q000187:drug effects*; D004594:Electrophysiology; D006634:Histamine H1 Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007262:Infusions, Intravenous; D008297:Male; D011802:Quinidine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016593:Terfenadine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D006634:Histamine H1 Antagonists; D016593:Terfenadine; D011802:Quinidine