IMPORTANCE OF PHARMACOKINETIC AND PHYSICOCHEMICAL DATA IN THE DISCOVERY AND DEVELOPMENT OF NOVEL ANTIARRHYTHMIC DRUGS

1. The importance of pharmacokinetics and physicochemical data in the discovery and development of a new mono-cationic antiarrhythmic agent, bidisomide (pK(a) 9.3), structurally related to the di-cationic anti- arrhythmic disobutamide (pK(a) of 8.6 and 10.2) and a mono-cationic dr ug disopyramide (pK(a) 10.4), is described. 2. In man, the di-cationic disobutamide was slowly eliminated with a mean terminal phase half-li fe of 54 +/- 18 h, a value > 7 times longer than disopyramide. The lon g terminal phase half-life of disobutamide is attributed to high accum ulation of the drug in the tissues, a phenomenon attributed to the di- cationic nature. 3. Structural modification of disobutamide resulted i n the mono-cationic agent bidisomide, designed to minimize drug accumu lation in the tissues. Human studies with bidisomide confirmed that th e terminal phase elimination of this drug was much faster than that of disobutamide, with a half-life of about 11 h. The absolute bioavailab ility of bidisomide was 45-62% which is lower than that of disopyramid e (60-90%). 4. Unlike disopyramide, absorption of bidisomide was compl ex, characterized by a lag period (0.75-1.5h) before absorption, follo wed by occurrence of two peaks in the plasma concentration-time curves . 5. The characteristic double peaks found with bidisomide was attribu ted to two rapid absorption sites of the drug in the gastrointestinal tract.