Prediction of human in vivo hepatic clearance from in vitro experiments in humans and rats and molecular descriptors of drugs

Abstract

Hepatic clearance is one of the most important pharmacokinetic parameters that affect ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) of drugs in human body, explaining metabolism and elimination steps among ADMET processes. The present study demonstrated that the information of molecular descriptors of drugs helps to increase the accuracy of prediction of human in vivo hepatic clearance from in vitro experimental data in humans and ats. Predictions were made for two datasets obtained from in vitro hepatocyte assay and in vitro microsome assay. I proposed a new method that combines experimental data and information of molecular descriptors of drugs. The prediction error and correlation between the predicted and observed values of the new method were compared with those of previous methods (methods using scaling factor, drug-specific scaling factor, and multiple linear regression analysis, respectively) that use experimental data only. Results showed that the new method was the most accurate prediction model with the lowest prediction errors and the strongest correlations for both datasets. In addition, the present study showed that (1) in vitro experimental data in humans and rats are important for predicting human in vivo hepatic clearance, (2) rat in vivo data are not essential for prediction, (3) the molecular descriptors are very useful to improve prediction accuracy, and (4) in vitro data in hepatocyte experiments are more useful than in microsome experiments. These results suggest that the information content of molecular descriptors is significant for the prediction of human in vivo pharmacokinetic parameter from in vitro experimental data. Since the present approach does not use in vivo animal data, application of the new method is most appropriate for predicting human pharmacokinetic parameters such as hepatic clearance by high-throughput. Prediction from only in vitro experimental data cuts down expenses and the time. The...