Plasma and myocardial tissue concentrations of UM-272 (N,N-dimethylpropranolol) after oral administration in dogs.
The oral absorption and effectiveness of UM-272, (N,N-dimethylpropranolol), 40 or 60 mg/kg, were evaluated in dogs in which ventricular tachycardia was produced by the administration of ouabain. Although both dosages were effective in converting ouabain-induced ventricular tachycardia to sinus rhythm, no relationship between plasma UM-272 concentrations and arrhythmia conversion or between UM-272 plasma concentrations and myocardial UM-272 concentrations was seen. The areas under the plasma concentration curve at conversion of ventricular tachycardia to sinus rhythm were similar for both dosage groups with area under the plasma concentration curve proportional to myocardial UM-272 concentration. Myocardial UM-272 concentrations were significantly lower in those animals demonstrating a reappearance of ventricular tachycardia during insulin-induced hypokalemia. Peak plasma UM-272 concentrations were 6 times greater, total area under the plasma UM-272 concentration curve 3 times greater and myocardial UM-272 concentrations more than twice as great in the 60 mg/kg group. These results suggest that systemic availability of UM-272 after oral administration is limited by the presence of a saturable process and that tissue uptake of UM-272 is time-dependent as well as concentration-dependent with cardiac tissue concentrations rather than plasma concentrations determining antiarrhythmic activity.
D000284:Administration, Oral; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000097:blood / Q000378:metabolism* / Q000627:therapeutic use; D004285:Dogs; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010042:Ouabain / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011433:Propranolol / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use; D013610:Tachycardia / Q000139:chemically induced / Q000188:drug therapy
D000889:Anti-Arrhythmia Agents; D010042:Ouabain; C002616:pranolium; D011433:Propranolol