Disposition of quinidine in the rabbit

Quinidine shows two-compartment characteristics in rabbits with a terminal half-life of 67 min for total drug and 58 min for unbound drug. Statistically, the values are not significantly different from each other (p greater than 0.05). The clearances for total and unbound drug are 52 and 464 ml/min/kg, respectively, and the total and unbound apparent volumes of distribution at steady state are 4.2 and 27.3 liters/kg, respectively. The unbound clearance and unbound apparent volume of distribution were inversely related to the unbound fraction of quinidine in plasma. The total clearance and apparent volume of distribution showed no relationship to the binding. Approximately 0.5% of the dose was excreted as unchanged quinidine. Six identifiable metabolites were found in the urine, accounting for approximately 14% of the dose. Two unknown metabolites were also observed in the urine. With the exception of 2'-quinidinone, these metabolites were formed in the rate-limiting step in the metabolite kinetics. The quinidine unbound fraction ranged from 0.06 to 0.23 in the eight rabbits studied. The binding of the metabolites was less pronounced, and only 3-hydroxyquinidine showed a significant correlation with quinidine binding.