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Comparative pharmacokinetics of quinidine and its O-desmethyl metabolite in rabbits.

The pharmacokinetics of quinidine and the O-desmethyl metabolite 6'-hydroxycinchonine were studied in rabbits. After intravenous bolus injections of equimolar doses, the blood concentration-time curves of each agent declined biexponentially, which was characteristic of a two-compartment open model. A significant difference between quinidine and 6'-hydroxycinchonine was observed for the following parameters: t1/2 alpha, beta, t1/w beta, k12, Vd beta, and the intercompartmental distribution ratio, k12/k21. The results showed that the distribution of the metabolite was slower than quinidine and suggested that it also was less extensive. The Vd beta value for 6'-hydroxycinchonine was approximately one-half of the value observed for quinidine, and its k12/k21 ration was about one-fourth of the quinidine value. The terminal half-lives for quinidine and the metabolite were 132.4 +/- 27.1 and 65.4 +/- 34.4 min, respectively. Total body clearance was similar for both compounds. The findings of this study could be explained by the greater polarity or greater water solubility of 6'-hydroxycinchonine. The limited data in humans coupled with the results of this investigation suggest that, although it is intrinsically active, the O-demethylated metabolite probably contributed little to the antiarrhythmic effects seen after quinidine administration in humans.