Antiarrhythmic effect related to the plasma concentration of pentisomide in vivo and the antiarrhythmic-concentration relationship in vitro.
Pentisomide, 2-(2-diisopropylaminoethyl)-4-methyl-2-(pyridyl)- pentanamide, is a novel antiarrhythmic agent structurally related to disopyramide. Using a glass bead arrhythmic model, the authors studied the antiarrhythmic effect of pentisomide in dogs by monitoring the plasma concentrations. When pentisomide was infused at 1 mg/kg/min for 20 min, the ventricular tachycardia was significantly reduced at 5 min after starting the infusion; the arrhythmias were reduced to less than 5% at the end of the 20 min infusion. The plasma-free concentration of pentisomide was about 3 micrograms/ml at 5 min; it increased to about 10 micrograms/ml at the end of 20 min infusion. With 0.3 mg/kg/min infusion, the arrhythmias were reduced to about 60% but were not significant at 20 min of infusion. The plasma-free concentration of pentisomide did not reach 3 micrograms/ml until 20 min of infusion. The 3 micrograms/ml plasma-free concentration for pentisomide seems to be a critical concentration in inducing a significant antiarrhythmic effect. Pentisomide dose-dependently inhibited ischaemia-reperfusion arrhythmia at doses of 30 microM and higher concentrations in vitro. In conclusion, pentisomide inhibits arrhythmias dependent with the plasma concentration or with the concentration of the external solution. The critical plasma-free concentration for inhibition of arrhythmias was 3 micrograms/ml (not equal to 10 microM) and the in vitro effect also had a similar concentration. Therefore, the in vivo and in vitro antiarrhythmic concentrations were well correlated.
Pharmaceutical Research Centre, Meiji Seika Kaisha Ltd., Yokohama, Japan.
M
M
Hachisu
H
H
Chen
T
T
Soneda
K
K
Fujishima
T
T
Ishizuka
F
F
Konno
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000097:blood* / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000209:etiology; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy; D011437:Propylamines / Q000097:blood* / Q000494:pharmacology*; D011725:Pyridines / Q000097:blood* / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D011437:Propylamines; D011725:Pyridines; C045930:propisomide