FLUID SHIFTS AND OTHER FACTORS AFFECTING PLASMA-PROTEIN BINDING OF PREDNISOLONE BY EQUILIBRIUM DIALYSIS
FLUID SHIFTS AND OTHER FACTORS AFFECTING PLASMA-PROTEIN BINDING OF PREDNISOLONE BY EQUILIBRIUM DIALYSIS
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DOI：
10.1002/jps.2600730617
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发表时间：
1984-01-01
影响因子：
3.8
通讯作者：
JUSKO, WJ
中科院分区：
文献类型：
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作者：
BOUDINOT, FD;JUSKO, WJ
通过平衡透析检查药物稳定性、放射性示踪剂纯度缓冲液组成、蛋白质浓度和液体转移对泼尼松龙的非线性人血浆蛋白结合的影响。泼尼松龙表现出浓度依赖性降解;然而，其有限程度不影响蛋白结合。用作示踪剂的不纯氚化泼尼松龙产生不正确的低分数结合值，其中针对皮质激素转运蛋白产生的结合参数比针对白蛋白产生的结合参数受影响更大。等渗磷酸钠和Krebs原始林格磷酸盐缓冲液产生相似的泼尼松龙结合分数和相同的蛋白结合参数。类固醇的结合分数随总血浆蛋白浓度而降低，但结合常数在血浆蛋白的2倍稀释度内保持恒定。进一步稀释会增加这些参数。透析过程中时间依赖性胶体渗透液转移导致血浆蛋白浓度稀释和药物结合减少。理论模拟表明，渗透液的变化产生的最大的变化，结合分数的化合物，结合的低容量蛋白质与低缔合常数（K < 106/M）。建立了一个数学方程，以校正结合药物浓度和结合分数，以用于由该效应引起的蛋白质稀释。向透析缓冲液中加入葡聚糖（MW 70，000），浓度为总蛋白浓度的55%，可防止液体转移。多种因素可以减少非线性泼尼松龙结合的伪影在平衡透析，但变化相对温和。
The effects of drug stability, radioactive tracer purity buffer composition, protein concentration, and fluid shifts on the nonlinear human plasma protein binding of prednisolone were examined by equilibrium dialysis. Prednisolone exhibits a concentration-dependent degradation; however, the limited extent of this does not affect protein binding. Impure tritiated prednisolone used as a tracer produces incorrect, low fractional binding values with the binding parameters generated for transcortin affected more than those for albumin. Isotonic sodium phosphate and Krebs original Ringer phosphate buffers yield similar fractional binding of prednisolone and identical protein binding parameters. Fractional binding of the steroid decreases with total plasma protein concentration but the association constants remain constant over a 2-fold dilution of plasma proteins. Further dilution increases these parameters. A time-dependent colloidal osmotic fluid shift during dialysis causes dilution of plasma protein concentrations and diminished drug binding. Theoretical simulations show that the osmotic fluid shifts produce the largest changes in fractional binding for compounds that are bound by low-capacity proteins with low association constants (K < 106/M). A mathematical equation was developed to correct bound drug concentratins and fraction bound for protein dilution caused by this effect. The fluid shifts can be prevented by the addition of dextran (MW 70,000) to the dialysis buffer in a concentration of 55% of the total protein concentration. Multiple factors can diminish the nonlinear prednisolone binding as artifacts during equilibrium dialysis, but the changes are relatively modest.