'Null method' determination of drug biophase concentration.
'Null method' determination of drug biophase concentration.
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“零法”测定药物生物相浓度。
DOI：
10.1007/s11095-011-0612-5
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发表时间：
2012
影响因子：
3.7
通讯作者：
Raffa,RobertB
中科院分区：
文献类型：
--
作者：
Tallarida,RonaldJ;Lamarre,Neil;Raffa,RobertB
通过改进其度量的准确性，PK/PD建模得到了增强。对于与酶或受体相互作用的药物和生物制剂的PK/PD建模，相互作用的平衡常数可以提供关键的见解。放射性有机体结合和分离组织制备等方法可以提供药物和内源性配体与特定酶和受体相互作用的平衡常数（如解离常数，k值）的估计。然而，进一步精确的PK/PD建模的一个障碍是，将散装溶液中的药物浓度(a)转换为受体占用的估计仍然是一个问题，因为根据质量作用定律，不一定是生物相中产生分数结合的药物浓度(C)，即。c /（c + k）在大多数实验研究中，它要大得多，所以使用给药而不是生物相浓度，分数占用率非常接近统一。我们在这里提供了一种简单的方法来获得在分离组织制备中将总药物浓度转化为生物相浓度的因子的估计。我们的方法是现在由Furchgott引入并应用于确定药物受体解离常数的经典“零法”的扩展。
PK/PD modeling is enhanced by improvements in the accuracy of its metrics. For PK/PD modeling of drugs and biologics that interact with enzymes or receptors, the equilibrium constant of the interaction can provide critical insight. Methodologies such as radioliogand binding and isolated tissue preparations can provide estimates of the equilibrium constants (as the dissociation constant,Kvalue) for drugs and endogenous ligands that interact with specific enzymes and receptors. However, an impediment to further precision for PK/PD modeling is that it remains a problem to convert the concentration of drug in bulk solution (A) into an estimate of receptor occupation, sinceAis not necessarily the concentration (C) of drug in the biophase that yields fractional binding from the law of mass action,viz.,C/(C + K). In most experimental studiesAis much larger thanK, so the use of administered instead of biophase concentration gives fractional occupancies very close to unity. We here provide a simple way to obtain an estimate of the factor that converts the total drug concentration into the biophase concentration in isolated tissue preparation. Our approach is an extension of the now classic ‘null method’ introduced and applied by Furchgott to determination of drug-receptor dissociation constants.