Kessler K M, Wozniak P M, McAuliffe D, Terracall E, Kozlovskis P, Mahmood I, Zaman L, Trohman R G, Castellanos A, Myerburg R J
Veterans Administration Medical Center, Miami, FL.
Am Heart J. 1989 Jul;118(1):63-9. doi: 10.1016/0002-8703(89)90073-2.
Pharmacodynamic and pharmacokinetic aspects pertinent to the potential clinical application of unbound quinidine levels were studied. Following heparin administration during electrophysiologic testing in 10 patients receiving quinidine, there were significant increases in the mean (+/- SD) right ventricular effective refractory period (266 +/- 24 versus 279 +/- 23; p less than 0.025), free fatty acid concentration (515 +/- 213 versus 1071 +/- 359 mmol/L; p less than 0.001), and unbound quinidine concentration (0.3 +/- 0.1 to 0.6 +/- 0.1 microgram/ml; p less than 0.001) but no changes in heart rate, corrected QT interval, or total plasma quinidine concentration. Ten control patients showed no change in the right ventricular effective refractory period following heparin administration. These findings were consistent with a heparin-induced increase in unbound drug concentration and activity that was limited to the vascular compartment. Eleven patients studied on day 3 (+/- 1) and day 10 (+/- 3) during an acute myocardial infarction showed a significant decrease in unbound quinidine fraction (12 +/- 4% versus 9 +/- 4%; p less than 0.02) accompanied by a decrease, rather than the predicted increase, in half-life (7.1 +/- 2.7 versus 6.3 +/- 2.1 hours; p less than 0.02). Volumes of distribution remained stable while the mean quinidine clearance tended to increase. Half-life correlated with albumin changes (r = -0.71; p less than 0.02). Apparently, improvement in clinical status (assumed) and drug clearance (measured) negated the direct effects of the decrease in unbound quinidine fraction. Although unbound drug concentrations should correlate best with drug dynamic and kinetic information, full knowledge of the clinical context of such measurements is needed for appropriate interpretation.
研究了与未结合奎尼丁水平潜在临床应用相关的药效学和药代动力学方面。在10例接受奎尼丁治疗的患者进行电生理测试期间给予肝素后，平均（±标准差）右心室有效不应期显著增加（266±24对279±23；p<0.025），游离脂肪酸浓度（515±213对1071±359 mmol/L；p<0.001），以及未结合奎尼丁浓度（0.3±0.1至0.6±0.1微克/毫升；p<0.001），但心率、校正QT间期或血浆总奎尼丁浓度无变化。10例对照患者在给予肝素后右心室有效不应期无变化。这些发现与肝素诱导的未结合药物浓度和活性增加一致，且仅限于血管腔室。11例在急性心肌梗死第3天（±1）和第10天（±3）进行研究的患者显示未结合奎尼丁分数显著降低（12±4%对9±4%；p<0.02），同时半衰期降低，而非预期的增加（7.1±2.7对6.3±2.1小时；p<0.02）。分布容积保持稳定，而平均奎尼丁清除率趋于增加。半衰期与白蛋白变化相关（r=-0.71；p<0.02）。显然，临床状况（假定）和药物清除率（测量）的改善抵消了未结合奎尼丁分数降低的直接影响。虽然未结合药物浓度应与药效学和药代动力学信息最佳相关，但为了进行适当的解释，需要充分了解此类测量的临床背景。
