In Silico Prediction of Human Renal Clearance of Compounds Using Quantitative Structure-Pharmacokinetic Relationship...

Renal clearance (CLr) plays an essential role in the elimination of drugs. In this study, 636 compounds were obtained from various sources to develop in silico models for the prediction of CLr. Stepwise multiple linear regression and random forest regression methods were employed to build global models and local models according to ionization state or net elimination pathways. The local models toward compounds undergoing different net elimination pathways showed good predictive power: the geometric mean fold error was close to 2, indicating the clearance of most compounds could be predicted within a 2-fold error range. Six classification methods were used to construct classification models. However, the performance of these classification models was less than satisfactory, and the mean accuracy of the top five models in test sets was 0.65. Moreover, qualitative analysis of physicochemical profiles between compounds undergoing different net elimination pathways revealed that compounds with higher lipophilicity tended to be reabsorbed more easily and showed lower CLr, while compounds with higher values of polar descriptors tended to secrete more easily and showed higher CLr.