Davies R F, Siddoway L A, Shaw L, Barbey J T, Roden D M, Woosley R L
University of Ottawa Heart Institute, Ontario, Canada.
Clin Pharmacol Ther. 1993 Jul;54(1):16-22. doi: 10.1038/clpt.1993.103.
To examine the effects of saturable plasma binding on the pharmacokinetics of immediate-release (IR) and controlled-release (CR) disopyramide.
Saturable binding causes a lack of correspondence between the pharmacokinetics of total and unbound plasma disopyramide. Levels of total drug may therefore be insensitive to important differences between formulations.
Patients receiving long-term disopyramide underwent serial blood sampling during withdrawal of equivalent doses of IR and CR disopyramide, and during accumulation of IR disopyramide. Plasma disopyramide was measured by enzyme-multiplied immunoassay technique, protein binding by ultrafiltration, and alpha 1-acid glycoprotein by radial immunodiffusion. Pharmacologic effect was assessed by use of high-speed ECGs. Values for plasma area under the concentration-time curve and elimination half-life were determined from the log-plasma concentration data; rate of plasma drug accumulation was determined by nonlinear modeling.
Saturable plasma binding was evident in all patients. Comparison of total to unbound drug showed that peak-to-trough ratios during steady state were smaller (1.45 versus 2.39; p < 0.001), elimination half-life was longer (12.1 versus 4.5 hours; p < 0.001), and the time to achieve 50% of steady-state levels during drug accumulation was shorter (8.1 versus 4.3 hours; p < 0.05). Comparison of IR and CR disopyramide showed that unbound drug levels for CR disopyramide revealed lower peak plasma concentrations (0.75 versus 0.96 micrograms/ml) and peak-to-trough ratios (1.83 versus 2.31; p < 0.001). Trough plasma concentrations were similar. Fluctuations in ECG intervals during usual dosing were observed only with IR disopyramide.
Because of saturable plasma binding, total plasma concentrations underestimate fluctuations in unbound disopyramide during usual dosing and are insensitive to significant differences between IR and CR formulations. CR disopyramide provides less interdose variation in free drug levels and more constant pharmacologic effects.
研究可饱和血浆蛋白结合对速释型（IR）和控释型（CR）丙吡胺药代动力学的影响。
可饱和蛋白结合导致血浆中总丙吡胺和游离丙吡胺的药代动力学缺乏对应关系。因此，总药物水平可能对不同剂型之间的重要差异不敏感。
接受长期丙吡胺治疗的患者在等量IR和CR丙吡胺撤药期间以及IR丙吡胺蓄积期间进行系列血样采集。采用酶倍增免疫分析技术测定血浆丙吡胺，超滤法测定蛋白结合率，放射免疫扩散法测定α1-酸性糖蛋白。通过高速心电图评估药理作用。根据血浆浓度对数数据确定血浆浓度-时间曲线下面积和消除半衰期的值；通过非线性模型确定血浆药物蓄积率。
所有患者均存在可饱和血浆蛋白结合。总药物与游离药物的比较显示，稳态时峰谷比更小（1.45对2.39；p<0.001），消除半衰期更长（12.1对4.5小时；p<0.001），药物蓄积期间达到稳态水平50%的时间更短（8.1对4.3小时；p<0.05）。IR和CR丙吡胺的比较显示，CR丙吡胺的游离药物水平显示出较低的血浆峰浓度（0.75对0.96微克/毫升）和峰谷比（1.83对2.31；p<0.001）。谷血浆浓度相似。仅在使用IR丙吡胺时观察到常规给药期间心电图间期的波动。
由于可饱和血浆蛋白结合，总血浆浓度低估了常规给药期间游离丙吡胺的波动，并且对IR和CR剂型之间的显著差异不敏感。CR丙吡胺在游离药物水平上提供了较小的剂量间差异和更恒定的药理作用。
