PHARMACOKINETICS OF ANTIARRHYTHMIC DISOPYRAMIDE IN HEALTHY HUMANS

The pharmacokinetics of the antiarrhythmic disopyramide, 4-diisopropylamino-2-phenyl-2-(2-pyridyl)butyramide phosphate and its monodealkylated metabolite were investigated in 7 volunteers after i.v. (1 and 2 mg/kg) and oral (3 and 6 mg/kg) administration. Unchanged drug (52%) and the monodealkylated metabolite (25%) were renally excreted on i.v. administration. The pharmacokinetics of disopyramide were 1st order and dose independent only when referenced to the drug not bound to plasma proteins since this binding was dose dependent. The apparent half-lives of the .alpha. and .beta. phases on i.v. administration were 2 min and 4.5 h, respectively. The apparent volumes of distribution of the central and peripheral compartments, referenced to unbound disopyramide in the plasma, were 9 and 80 l, respectively. The half-life of absorption of oral aqueous disopyramide phosphate was 30 min with a lag time of 16 min and an apparent 1st-pass metabolism of 16% of the absorbed dose, consistent with the hepatic efficiency of 14%. The renal and metabolic clearances were 125 and 111 ml/min, respectively. Graphical and computer analysis of the plasma and urine data showed dose-independent 1st-order pharmacokinetics of plasma unbound drug in a 2-compartment-body model which gave 2 metabolites and a 1st-pass transformation of a fraction of the oral dose. The absorption efficiency of unchanged drug was 83%.