Pharmacodynamics of 3-hydroxyquinidine alone and in combination with quinidine in healthy persons

Abstract

The relation between serum concentration of 3-hydroxyquinidin (3-OHO), a major metabolite of quinidine in humans, and the pharmacologic effect alone and in combination with the parent drug was studied. The heart rate-corrected, computer-averaged QT interval (QTc) was used as the pharmacologic endpoint. In a randomized, double-blind study, 5 healthy subjects received, on 3 separate days 1 week apart, either (1) 300 to 400 mg 3-OHO orally or (2) 150 mg quinidine base intravenously or (3) a combination in the same doses. Blood samples and electrocardiographic recordings were obtained over the following 10 hours. Serum concentrations of 3-OHO and quinidine were determined by high-pressure liquid chromatography and the free fraction by ultrafiltration. Peak concentrations of 3-OHO varied between 1,362 and 3,480 ng/ml after oral 3-OHQ ingestion, but were negligible after intravenous quinidine infusion. The free fraction was 49% ± 4.8 (mean ± standard deviation) for 3-OHO and 20% ± 4.3 for quinidine. In all 5 subjects a statistically significant correlation was found between serum concentration and QTc prolongation for both quinidine and 3-OHQ (largest p value <0.025). The mean slope of the regression line was 0.0184 ± 0.0128 for 3-OHO and 0.0297 ± 0.0111 for quinidine. Multiple linear regression revealed in each subject a significant additive effect of 3-OHQ when administered together with quinidine (largest p value <0.05). When the compounds were administered in combination, the slope of the concentration-effect relation was 0.0122 ± 0.0041 for 3-OHO and 0.0276 ± 0.0077 for quinidine, indicating that in the concentration range studied, the effective of the metabolite and the parent drug were additive.