Classification of Inhibitors of Hepatic Organic Anion Transporting Polypeptides (OATPs): Influence of Protein Expression on Drug–Drug Interactions

The hepatic organic anion transporting polypeptides (OATPs)
influence the pharmacokinetics of several drug classes and are involved
in many clinical drug–drug interactions. Predicting potential
interactions with OATPs is, therefore, of value. Here, we developed
in vitro and in silico models for identification and prediction of
specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1.
The maximal transport activity (MTA) of each OATP in human liver was
predicted from transport kinetics and protein quantification. We then
used MTA to predict the effects of a subset of inhibitors on atorvastatin
uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP
inhibitors were identified. In silico models indicated that lipophilicity
and polar surface area are key molecular features of OATP inhibition.
MTA predictions identified OATP1B1 and OATP1B3 as major determinants
of atorvastatin uptake in vivo. The relative contributions to overall
hepatic uptake varied with isoform specificities of the inhibitors.