Prediction of steady-state volume of distribution of acidic drugs by quantitative structure-pharmacokinetics relationships.

The volume of distribution (VD) is one of the most important pharmacokinetic parameters of drugs. The present study employs quantitative structure-pharmacokinetics relationships (QSPkR) to derive models for VD prediction of acidic drugs. The steady-state volume of distribution (VD(ss)) values of 132 acidic drugs were collected, the chemical structures were described by 178 molecular descriptors, and QSPkR models were derived after variable selection by genetic algorithm and stepwise regression. Models were validated by cross-validation procedures and external test set. According to the molecular descriptors selected as the most predictive for VD(ss), the presence of seven- and nine-member cycles, atom type P(5+), SH groups, and large nonionized substituents increase the VD(ss), whereas atom types S(2+) and S(4+) and polar ionized substituents decrease it. Cross-validation and external validation studies on the QSPkR models derived in the present study showed good predictive ability with mean fold error values ranging from 1.58 (cross-validation) to 2.25 (external validation). The model performance is comparable to more complicated methods requiring in vitro or in vivo experiments and superior to the existing QSPkR models concerning acidic drugs. Apart from the prediction of VD in human, present models are also useful as a curator of available pharmacokinetic databases.