Pharmacokinetics and pharmacodynamics of (+/-)-sotalol in healthy male volunteers.
1. We investigated the pharmacokinetics and pharmacodynamics of (+/-)-sotalol administered orally to healthy male volunteers in single doses of 40, 80 and 160 mg and in multiple doses of 80 mg twice daily for 7 consecutive days. 2. In the single dose studies, the half-life of (-)-sotalol (7.2-8.5 h) was significantly (P < 0.01) shorter than that of (+)-sotalol (9.1-11.4 h) while the renal clearance of (-)-sotalol (110.6-126.4 ml min-1) was significantly (P < 0.01) faster than that of (+)-sotalol (102.2-110.1 ml min-1). In the multiple dose studies, similar differences in the pharmacokinetics of (+)- and (-)-sotalol were observed. In addition, the pharmacokinetics of both (+)- and (-)-sotalol on day 4 were shown to be essentially the same as those on day 7. 3. In pharmacodynamic examinations, (+/-)-sotalol prolonged QTc intervals on electrocardiograms dose-dependently after single doses of 80 and 160 mg (3.81 +/- 2.96%, 13.23 +/- 5.66%). The correlation between the plasma concentration of (+/-)-sotalol and prolongation of QTc intervals was nearly linear, and showed no hysteresis. 4. In conclusion, we demonstrated that QTc interval was prolonged with a linear correlation to the plasma concentration of (+/-)-sotalol. In addition, our study suggested that differences in the pharmacokinetics of (+)- and (-)-sotalol may be attributable to faster urinary excretion of (-)-sotalol.
Kimura
M
M
Department of Clinical Pharmacology, Hamamatsu University School of Medicine, Kanagawa, Japan.
Umemura
K
K
Ikeda
Y
Y
Kosuge
K
K
Mizuno
A
A
Nakanomyo
H
H
Ohashi
K
K
Nakashima
M
M
D000284:Administration, Oral; D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D006801:Humans; D008297:Male; D008875:Middle Aged; D013015:Sotalol / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D013237:Stereoisomerism
D000889:Anti-Arrhythmia Agents; D013015:Sotalol