Drug Distribution Part 2. Predicting Volume of Distribution from Plasma Protein Binding and Membrane Partitioning.
Drug Distribution Part 2. Predicting Volume of Distribution from Plasma Protein Binding and Membrane Partitioning.
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DOI：
10.1007/s11095-016-2086-y
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发表时间：
2017-03
影响因子：
3.7
通讯作者：
Nagar S
中科院分区：
文献类型：
--
作者：
Korzekwa K;Nagar S
分布容积是药物分布和半衰期的重要药代动力学参数。蛋白结合和脂质分配共同决定药物分布。在这里，我们提出了一个简单的关系，估计分布容积与血浆和微粒体中未结合药物的分数。模型方程基于双室系统，血浆和微粒体中未结合的实验级分分别代表与血浆蛋白和细胞脂质的结合。使用包含63种药物的人体体外和体内参数的数据集对蛋白质和脂质结合组分进行参数化。所得方程解释了分布容积对数中约84%的方差，平均误差倍数为1.6，有3个离群值。这些结果表明，Vss可以预测大多数药物从血浆蛋白结合和微粒体分配。
Volume of distribution is an important pharmacokinetic parameter in the distribution and half-life of a drug. Protein binding and lipid partitioning together determine drug distribution. Here we present a simple relationship that estimates the volume of distribution with the fraction of drug unbound in both plasma and microsomes. Model equations are based upon a two-compartment system and the experimental fractions unbound in plasma and microsomes represent binding to plasma proteins and cellular lipids, respectively. The protein and lipid binding components were parameterized using a dataset containing human in vitro and in vivo parameters for 63 drugs. The resulting equation explains ~84% of the variance in the log of the volume of distribution with an average fold-error of 1.6, with 3 outliers. These results suggest that Vss can be predicted for most drugs from plasma protein binding and microsomal partitioning.