Effects of sex on the pharmacokinetic and pharmacodynamic properties of quinidine

• Published in: British journal of clinical pharmacology Vol. 56; no. 2; pp. 198 - 204
• Main Authors: El‐Eraky, Hala, Thomas, Simon H. L.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.08.2003; Blackwell Science; Blackwell Science Inc
• Subjects: Administration, Oral; Adolescent; Adult; Anti-Arrhythmia Agents - adverse effects; Anti-Arrhythmia Agents - blood; Anti-Arrhythmia Agents - pharmacokinetics; Biological and medical sciences; cardiac repolarization; Drug toxicity and drugs side effects treatment; Electrocardiography; Female; Heart Rate - drug effects; Humans; long QT syndrome; Long QT Syndrome - chemically induced; Male; Medical sciences; Middle Aged; Pharmacokinetics; Pharmacology. Drug treatments; Quinidine - adverse effects; Quinidine - blood; Quinidine - pharmacokinetics; sex; Sex Characteristics; torsade de pointes; Torsades de Pointes - chemically induced; Toxicity: cardiovascular system; Human; QT interval; Wave burst; Arrhythmia; Healthy subject; long QT syndrome; Single dose; Prolonged QT interval; Sex; Oral administration; Cardiovascular disease; Male; Antiarrhythmic agent; Conduction disorder; Excitability disorder; Heart block; Heart disease; Quinidine; Electrocardiography; cardiac repolarization; Female; torsade de pointes; Pharmacokinetics
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1046/j.1365-2125.2003.01865.x

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.