Abstract
1. Biliary excretion of compounds is dependant on several transporter proteins for the active uptake of compounds from the blood into the hepatocytes. Organic anion-transporting polypeptides (OATPs) are some of the most abundant transporter proteins in the sinusoidal membrane and have been shown to have substrate specificity similar to the structural characteristics of cholephilic compounds.
2. In this study, we sought to use measures of OATP binding as predictors of biliary excretion in conjunction with molecular descriptors in a quantitative structure-activity relationship (QSAR) study. Percentage inhibitions of three subtypes of OATPs were used as surrogate indicators of OATP substrates. Several statistical modelling techniques were incorporated including classification and regression trees, boosted trees, random forest and multivariate adaptive regression splines (MARS) in order to first develop QSARs for the prediction of OATP inhibition of compounds. The predicted OATP percentage inhibition using selected models were then used as features of the QSAR models for the prediction of biliary excretion of compounds in rat.
3. The results indicated that incorporation of predicted OATP inhibition improves accuracy of biliary excretion models. The best result was obtained from a simple regression tree that used predicted OATP1B1 percentage inhibition at the root node of the tree.
Acknowledgements
The authors gratefully acknowledge the NIH Fellows Editorial Board for constructive comments, careful review of this manuscript, support and assistance for this work. M. Sharifi would like to thank Dr Jon Wilkes and Dr Dan Buzatu for support and valuable comments and also Oak Ridge Institute for Science and Education (ORISE) for support.
Declaration of interest
The authors declare no conflict of interest. The views presented in this article are those of the authors and do not necessarily reflect those of the US Food and Drug Administration. No official endorsement is intended nor should be inferred.
Supplementary material available online