lbutilide fumarate is a class Ill antiarrhythmic agent in phase Ill clinical trials. Due to rapid hepatic metabolism, ibutilide has a low oral bioavailability (< 10%). To assess alternate routes of administration, we performed repeated studies of the electrophysiologic effects of sublingual ibutilide (0.03, 0.1, and 0.3 mgikg; 0.07, 0.2, and 0.7 pmolikg) in pentobarbital anesthetized dogs. Peak significant increases in QTc interval, ventricular effective refractory period (VERP), and right ventricular monophasic action potential duration (MAPD90) were achieved 30 min following 0.1 or 0.3 mg/kg (0.2 and 0.7 pmolikg) ibutilide and were coincident with peak plasma ibutilide levels. The duration of significant effects ranged from 2 to 5 h. Peak effects were: QTc + 121 msec, MAPD90 +71 msec, and VERP +53 msec. The 0.3 mgikg (0.7 pmol) dose significantly decreased heart rate 10 min post dosage through 5 h. The 0.03 mgikg (0.07 +mol) dose increased MAPD30 at 1 to 2 h but was otherwise ineffective. The plasma half life of ibutilide was 2.8 h, with a 72% bioavailability relative to an equivalent intravenous dose. Based dn the electrophysiologic results, we chose to test the 0.1 mg/kg (0.2 pmol) sublingual ibutilide dose for termination of sustained atrial flutter in anesthetized dogs with y-shaped right atrial incisions. The administration of 0.1 mg/kg (0.2 pmol) sublingual ibutilide during sustained atrial flutter resulted in termination of atrial flutter in all cases (n = 4) after a mean time interval of 11.4 k 0.8 min. Termination of atrial flutter was associated with ibutilide plasma levels of 19.6 k 6.3 ng/ml, and 30 and 18 msec increases in atrial and ventricular effective refractory periods. Atrial flutter could be reinduced in 2 dogs, one at 3 h and one at 4 h post ibutilide administration. The ability to reinduce atrial flutter was associated with a reduction in ibutilide plasma levels to 2.3 ? 0.7 ng/ml. We conclude that sublingual ibutilide i s rapidly absorbed and produces significant electrophysiologic and antiarrhythmic effects, and i s a potential alternative to intravenous and oral therapy. D 1995 Wiiey-Liss, Inr