EFFECTS OF CHRONIC ETHANOL INGESTION ON PHARMACOKINETICS OF PROCAINAMIDE IN RATS

Blood level studies were carried out in rats to determine the effects of chronic ethanol ingestion on the distribution pharmacokinetic parameters and tissue steady-state partition coefficients of procainamide. The ethanol-treated rats received 4g/kg of ethanol daily for 28 days in Treatment A and 4 g/kg of ethanol for an initial 7 days, followed by 8 g/kg of ethanol for the subsequent 21 days in Treatment B; the control rats received isocaloric sucrose in the respective groups. As determined from two-compartment analysis of the blood level data, both ethanol treatments significantly decreased the distribution clearance (CL(d); k12 Vd(c)) and the apparent first-order rate constant for drug transfer from the central compartment to the tissue compartment (k12) of procainamide without affecting the total body clearance of drug (CL) or the apparent volumes of distribution of drug in the body at steady state (Vd(ss)) and at pseudo-equilibrium (Vd-beta). Additionally, the apparent volume of distribution of the drug in the central compartment (Vd(c)) was 57-62% greater due to both ethanol treatments. Furthermore, the steady-state partition coefficients of the drug were found to be significantly lower in heart and kidneys and greater in fat of the ethanol-treated rats (Treatment B) as compared with those in the control rats. Possible mechanisms are proposed to account for these various effects in light of the known effects of chronic ethanol ingestion on the chemical composition of cell membranes of tissues and organs.