PURPOSE: To develop a QSAR model, based on calculated molecular descriptors and an Artificial Neural Networks Ensemble (ANNE), for the estimation of rat tissue-to-blood partition coefficients (Kt:b), as well as the assessment of the applicability domain of the model and its utility in predicting the drug distribution in humans. METHODS: A total of 1460 individual Kt:b values (75% train and 25% validation), obtained in 13 different rat tissues were collected in the literature. A correlation between simple molecular descriptors for lipophilicity, ionization, size and hydrogen bonding capacity and Kt:b data was attempted by using an ANNE. RESULTS: Similar statistics were observed between the train and validation group of data with correlations, between the observed values and the predicted average ANNE values, of 0.909 and 0.896, respectively. A degradation of the correlations was observed for predicted values with high uncertainty, as judged by the standard deviations of the ANNE outputs. This was further observed when using the ANNE Kt:b values in a Physiologically based pharmacokinetic (PBPK) model for predicting the Human Volume of distribution of another 532 drugs. CONCLUSIONS: This model (available as a MS Excel® workbook in the Supporting material of this article) may be a valuable tool for prediction and simulation in early drug development, allowing the in silico estimation of rat Kt:b values for PBPK purposes and also indicating its applicability domain.
PURPOSE: To develop a QSAR model, based on calculated molecular descriptors and an Artificial Neural Networks Ensemble (ANNE), for the estimation of rat tissue-to-blood partition coefficients (Kt:b), as well as the assessment of the applicability domain of the model and its utility in predicting the drug distribution in humans. METHODS: A total of 1460 individual Kt:b values (75% train and 25% validation), obtained in 13 different rat tissues were collected in the literature. A correlation between simple molecular descriptors for lipophilicity, ionization, size and hydrogen bonding capacity and Kt:b data was attempted by using an ANNE. RESULTS: Similar statistics were observed between the train and validation group of data with correlations, between the observed values and the predicted average ANNE values, of 0.909 and 0.896, respectively. A degradation of the correlations was observed for predicted values with high uncertainty, as judged by the standard deviations of the ANNE outputs. This was further observed when using the ANNE Kt:b values in a Physiologically based pharmacokinetic (PBPK) model for predicting the Human Volume of distribution of another 532 drugs. CONCLUSIONS: This model (available as a MS Excel® workbook in the Supporting material of this article) may be a valuable tool for prediction and simulation in early drug development, allowing the in silico estimation of rat Kt:b values for PBPK purposes and also indicating its applicability domain.
Authors: Terry R Stouch; James R Kenyon; Stephen R Johnson; Xue-Qing Chen; Arthur Doweyko; Yi Li Journal: J Comput Aided Mol Des Date: 2003 Feb-Apr Impact factor: 3.686
Authors: Igor V Tetko; Johann Gasteiger; Roberto Todeschini; Andrea Mauri; David Livingstone; Peter Ertl; Vladimir A Palyulin; Eugene V Radchenko; Nikolay S Zefirov; Alexander S Makarenko; Vsevolod Yu Tanchuk; Volodymyr V Prokopenko Journal: J Comput Aided Mol Des Date: 2005-06 Impact factor: 3.686