Effects of sex on the pharmacokinetic and pharmacodynamic properties of quinidine

Aims To investigate the source of the apparent increased susceptibility of women to develop QT interval prolongation and torsade de pointes after the administration of drugs that delay cardiac repolarization. Methods Plasma quinidine concentrations and electrocardiographic changes (QRS and QT intervals) were measured over 24 h following the administration of single oral doses of the QT prolonging drug quinidine (3 mg kg(-1)) and compared between 27 male and 21 female healthy volunteers. Results There were no significant differences between males and females in plasma quinidine concentrations or in calculated pharmacokinetic variables. Maximum quinidine concentrations in males and females were 997+/-56 and 871+/-57 ng ml(-1), respectively (mean difference (-125, 95% confidence intervals (CI) -239, 11 ng ml(-1), P=NS). Quinidine lengthened actual (QTa) and corrected (QTc) QT intervals and the QRS interval to a greater extent in females than males (P<0.001 for each), but there were no significant sex differences detected in the effects of quinidine on the heart rate corrected JT interval. Maximum prolongation of QTc interval was observed 2 h after quinidine and was significantly greater in women (33±16 vs 24±17 ms, mean difference 9±20 ms, 95% CI 3, 15, P=0.037). At this time mean differences (95% CI) were 1.0 min(-1) (-2.5, 4.4, P=NS) for heart rate, 5.5 ms (3.5, 7.6, P=0.05) for the QRS and 3.4 ms (-2.5, 9.3, P=NS) for the JTc intervals. Conclusions Quinidine-induced increases in QTc were larger in females, but no sex differences in quinidine pharmacokinetics were found. The disparity in prolongation of cardiac repolarization is thus due to a pharmacodynamic difference which appears more complex than simply an increase in repolarization delay in females.