IN SILICO QUANTITATIVE STRUCTURE – PHARMACOKINETIC RELATIONSHIP MODELING ON ACIDIC DRUGS: HALF LIFE
Zvetanka Dobreva Zhivkova, Irini Atanas Doytchinova · International Journal of Pharmacy and Pharmaceutical Sciences · 2014
Objective: Drug half-life ( t 1/2 ) is one of the key pharmacokinetic parameters for establishment of dosing regimen. Surprisingly, the relationship between the chemical structure and t 1/2 is still poorly explored. The aim of the present study is to derive quantitative structure – pharmacokinetic relationships (QSPkRs) for t 1/2 of acidic drugs. Methods: The dataset consisted of 142 molecules which were described with 187 structural and physicochemical descriptors. A three step variable selection procedure was applied to identify the most reliable descriptors. QSPkR modeling was performed using multivariate regression analysis (MLR). Results: A number of sound and robust QSPkR models were derived. The predictive ability of the models was tested by internal and external validation procedure. The most frequently emerged descriptors were used for construction of a consensus model for t 1/2 prediction. The model is statistically significant (explained variance 0.688) and predictive (cross validation correlation coefficient 0.600, mean fold error of prediction 2.06, accuracy 61%). It reveals the main structural features affecting t 1/2 . A short check list was proposed determining the cutoff between short half life ( t 1/2 24 h) drugs. Conclusion: The presence of a sulfonyl or phosphonate groups, non-polar substituents at aromatic carbon, 9- or 10-member ring system and donor-acceptor pair separated by 9 skeletal bonds contribute to prolongation of t 1/2 , while the presence of methane group, polar substituents at aromatic carbon and 7-member ring system affect negatively t 1/2 .