Importance of pharmacokinetic and physicochemical data in the discovery and development of novel anti-arrhythmic drugs

Abstract

1. The importance of pharmacokinetics and physicochemical data in the discovery and development of a new mono-cationic antiarrhythmic agent, bidisomide (pKa 9.3), structurally related to the di-cationic anti-arrhythmic disobutamide (pKa of 8.6 and 10.2) and a mono-cationic drug disopyramide (pKa 10.4), is described. 2. In man, the di-cationic disobutamide was slowly eliminated with a mean terminal phase half-life of 54 +/- 18 h, a value > 7 times longer than disopyramide. The long terminal phase half-life of disobutamide is attributed to high accumulation of the drug in the tissues, a phenomenon attributed to the di-cationic nature. 3. Structural modification of disobutamide resulted in the mono-cationic agent bidisomide, designed to minimize drug accumulation in the tissues. Human studies with bidisomide confirmed that the terminal phase elimination of this drug was much faster than that of disobutamide, with a half-life of about 11h. The absolute bioavailability of bidisomide was 45-62% which is lower than that of disopyramide (60-90%). 4. Unlike disopyramide, absorption of bidisomide was complex, characterized by a lag period (0.75-1.5 h) before absorption, followed by occurrence of two peaks in the plasma concentration-time curves. 5. The characteristic double peaks found with bidisomide was attributed to two rapid absorption sites of the drug in the gastrointestinal tract.

Design of drugs involving the concepts and theories of drug metabolism and pharmacokinetics

“…High accumulation of drug in tissues has also been implicated in the 5-to 7-times longer elimination half-life of the dibasic antiarrhythmic, disobutamide compared to the monobasic agents, disopyramide and bidisomide. 21 It is important to note that in these latter two examples, the high tissue affinity of the well tolerated, anti-infective, azithromycin, is viewed as a pharmacokinetic advantage, while similar high tissue affinity is viewed as disadvantageous for the low safety margin, antiarrhythmic, disobutamide. Obviously, different therapeutic areas impose different restrictions on the ideal pharmacokinetic profile for management of each condition, hence careful consideration should be paid to this at an early stage in drug discovery programs.…”

Distribution

“…Unbound clearance is essentially similar (10 ml/min/kg), but the free unbound volume is increased approximately 10-fold (4-40 l/kg) with a corresponding increase in half-life (3-37 h) [22]. Disobutamide has been shown to accumulate extensively in tissues in contrast to disopyramide [23].…”