Quantitative Structure – Pharmacokinetics Relationships Analysis of Basic Drugs: Volume of Distribution

Abstract

Purpose. The early prediction of pharmacokinetic behavior is of paramount importance for saving time and resources and for increasing the success of new drug candidates. The steady-state volume of distribution (VD_ss) is one of the key pharmacokinetic parameters required for the design of a suitable dosage regimen. The aim of the study is to propose a quantitative structure – pharmacokinetics relationships (QSPkR) for VD_ss of basic drugs. Methods: The data set consists of 216 basic drugs, divided to a modeling (n = 180) and external validation set (n = 36). 179 structural and physicochemical descriptors are calculated using validated commercial software. Genetic algorithm, stepwise regression and multiple linear regression are applied for variable selection and model development. The models are validated by internal and external test sets. Results: A number of significant QSPkRs are developed. The most frequently emerged descriptors are used to derive the final consensus model for VD_ss with good explanatory (r² 0.663) and predictive ability (q²_LOO-CV 0.606 and r²_pred 0.593). The model reveals clear structural features determining VD_ss of basic drugs which are summarized in a short list of criteria for rapid discrimination between drugs with a large and small VD_ss. Conclusions: Descriptors like lipophilicity, fraction ionized as a base at pH 7.4, number of cycles and fused aromatic rings, presence of Cl and F atoms contribute positively to VD_ss, while polarity and presence of strong electrophiles have a negative effect.

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