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In Silico Quantitative Structure Pharmacokinetic Relationship Modeling on Aryl Carboxylic Acid: Volume of Distribution and Serum Protein Binding

Bhupinder Singh, Priyadeep, Aman Singla and Yash Paul

An estimate of volume of distribution (Vd) and serum protein binding (% SPB) is of paramount importance in assessing the efficacy of drugs used to treat acute conditions like pain, which can be treated by a single dose. This study was conducted to develop Quantitative Structure Pharmacokinetic Relationship (QSPR) for the prediction of Vd and % SPB in men for congeneric series of twelve arylcarboxylic acid derivatives, using computer assisted Hansch approach. The QSPR correlations were duly analyzed using a battery of apt statistical procedures and validated using leave-one-out (LOO) approach. Analysis of several hundreds of QSPR correlations developed in this study revealed high degree of cross-validated coefficients (Q2) using LOO method (p < 0.001). The overall predictability was found to be high in case of Vd (R2 = 0.9846 F = 117.51 S2 = 0.0007, Q2 = 0.9617 p < 0.001) as well as % SPB (R2 = 0.9764 F = 204.31 S2 = 0.0942, Q2 = 0.9684 p < 0.001). Topological and steric parameters were found to primarily ascribe the variation in Vd and % SPB. The results indicated the involvement of dissolution rate limited absorption rather than permeation limited, as hardly any dependence on Log P was observed.