Pharmacokinetic and clinical implications of quinidine protein binding.
Pharmacokinetic and clinical implications of quinidine protein binding.
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奎尼丁蛋白结合的药代动力学和临床意义。
DOI：
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发表时间：
1979
期刊：
影响因子：
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通讯作者：
D. J. Greenblatt
中科院分区：
文献类型：
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作者：
E. Woo;D. J. Greenblatt
使用平衡透析来评估影响奎尼丁与血清蛋白结合的因素。结合不受-20°下长时间储存或临床相关范围内总血清奎尼丁浓度变化的影响。蛋白质结合随着温度在 24° 至 37° 之间的升高而降低 (p < 0.001)，并且当用磷酸盐缓冲液稀释将总血清蛋白浓度从 6.0 g/100 ml 降低至 2.6 g/100 ml 时。添加治疗浓度的水杨酸、保泰松和甲苯磺丁脲显着降低了奎尼丁结合 (p < 0.025)，但其他 10 种常用药物的结合却没有显着降低。水杨酸对奎尼丁的置换是非线性的；位移程度随着奎尼丁总浓度的增加而增加。 12 名健康受试者中未结合的奎尼丁分数几乎相差两倍，部分原因是血清白蛋白浓度在通常正常范围内（3.9-4.8 g/100 ml）内的差异。对 12 名接受单次静脉注射乳酸奎尼丁的志愿者的同时总血清奎尼丁浓度和未结合血清奎尼丁浓度进行药代动力学分析。总奎尼丁和未结合奎尼丁的平均消除半衰期没有显着差异。然而，未结合的奎尼丁的平均分布体积和总代谢清除率明显大于使用总药物浓度确定的结果。游离奎尼丁的肾清除率超过肌酐清除率，与未结合部分的肾小管分泌一致。当分析游离血清浓度而不是分析总血清浓度时，奎尼丁消除半衰期和代谢清除率的受试者间变异较小。静脉注射奎尼丁引起的急性心电图变化与未结合药物浓度的相关性优于与总药物浓度的相关性。因此，未结合和总血清奎尼丁浓度的测量可以提供对奎尼丁药代动力学和临床效果个体之间差异的额外理解。
Equilibrium dialysis was used to assess factors influencing quinidine binding to serum proteins. Binding was not influenced by prolonged storage at − 20° or by variation in total serum quinidine concentrations over a clinically relevant range. Protein binding decreased with increasing temperature between 24 and 37° (p < 0.001) and when total serum protein concentrations were decreased from 6.0 to 2.6 g/100 ml by dilution with phosphate buffer. The addition of therapeatic concentrations of salicylic acid, phenylbutazone, and tolbutamide significantly reduced quinidine binding (p < 0.025), but 10 other commonly coadministered drugs did not. Displacement of quinidine by salicylic acid was nonlinear; the extent of displacement increased with increasing total quinidine concentrations. The unbound quinidine fraction among 12 healthy subjects varied almost twofold and was partly explained by differences in serum albumin concentrations within the usual range of normal (3.9–4.8 g/100 ml). Pharmacokinetic analysis was performed on simultaneous total and unbound serum quinidine concentrations in 12 volunteers who received single intravenous doses of quinidine lactate. The mean elimination half-lives of total and unbound quinidine were not significantly different. However, the mean volume of distribution and total metabolic clearance of unbound quinidine were considerably greater than those determined using total drug concentrations. Renal clearance of free quinidine exceeded creatinine clearance, consistent with tubular secretion of the unbound fraction. Between-subject variability in elimination half-life and metabolic clearance of quinidine was less when free rather than total serum concentrations were analyzed. Acute ECG changes due to intravenous quinidine correlated better with unbound than with total drug concentrations. Thus, measurement of unbound as well as total serum quinidine concentrations may provide additional understanding of variations between individuals in pharmacokinetics and clinical effects of quinidine.