IN SILICO QUANTITATIVE STRUCTURE - PHARMACOKINETIC RELATIONSHIP MODELING ON ACIDIC DRUGS: HALF LIFE
Keywords:
Computational ADME, Half-life prediction, In silico modeling, QSPkR, MLR, Acidic drugsAbstract
Objective: Drug half-life (t1/2) is one of the key pharmacokinetic parameters for establishment of dosing regimen. Surprisingly, the relationship between the chemical structure and t1/2 is still poorly explored. The aim of the present study is to derive quantitative structure – pharmacokinetic relationships (QSPkRs) for t1/2 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 t1/2 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 t1/2. A short check list was proposed determining the cutoff between short half life (t1/2 < 1 h) and long half life (t1/2 > 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 t1/2, while the presence of methane group, polar substituents at aromatic carbon and 7-member ring system affect negatively t1/2.
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