Department of Discovery Toxicology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA.
Chem Res Toxicol. 2010 Apr 19;23(4):749-55. doi: 10.1021/tx9003825.
Drug-induced phospholipidosis (PLD) is an adaptive histologic alteration that is seen with various marketed drugs and often encountered during drug development. Various in silico and in vitro cell-based methods have been developed to predict the PLD-inducing potential of compounds. These methods rely on the inherent physicochemical properties of the molecule and, as such, tend to overpredict compounds as PLD inducers. Recognizing that the distribution of compounds into tissues or tissue accumulation is likely a key factor in PLD induction, in addition to key physicochemical properties, we developed a model to predict PLD in vivo using the measures of basicity (pK(a)), lipophilicity (ClogP), and volume of distribution (V(d)). Using sets of PLD inducers and noninducers, we demonstrate improved concordance with this method. Furthermore, we propose a screening paradigm that includes a combination of various methods to predict the in vivo PLD-inducing potential of compounds, which may be especially useful in lead identification and optimization processes in drug discovery.
药物诱导的磷脂病（PLD）是一种适应性组织学改变，可见于各种上市药物，并且在药物开发过程中经常遇到。已经开发了各种基于计算机的和基于细胞的体外方法来预测化合物的 PLD 诱导潜力。这些方法依赖于分子的固有物理化学特性，因此往往会过高地预测化合物作为 PLD 诱导剂。我们认识到，除了关键的物理化学特性外，化合物在组织中的分布或组织积累可能是诱导 PLD 的关键因素，因此我们开发了一种使用碱度（pKa）、亲脂性（ClogP）和分布体积（Vd）的指标来预测体内 PLD 的模型。我们使用一组 PLD 诱导剂和非诱导剂证明了该方法的一致性得到了提高。此外，我们提出了一种筛选范式，包括结合各种方法来预测化合物的体内 PLD 诱导潜力，这在药物发现的先导化合物识别和优化过程中可能特别有用。
