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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.

Purpose: To establish in vitro and in silico models that predict clinical drug-drug interactions (DDIs) with the OATP1B1 (SLCO1B1) transporter., Methods: The inhibitory effect of 146 drugs and drug-like compounds on OATP1B1-mediated transport was studied in HEK293 cells. A computational model was developed to predict OATP1B1 inhibition. Concentration-dependent effects were investigated for six compounds; clinical DDIs were predicted by calculating change in exposure (i.e. R-values) in eight different ways., Results: Sixty-five compounds were identified as OATP1B1 inhibitors at 20 μM. The computational model predicted the test set with 80% accuracy for inhibitors and 91% for non-inhibitors. In vitro-in vivo comparisons underscored the importance of using drugs with known clinical effects as references. Thus, reference drugs, cyclosporin A, gemfibrozil, and fenofibrate, provided an inhibition interval to which three antiviral drugs, atazanavir, lopinavir, and amprenavir, could be compared and their clinical DDIs with OATP1B1 classified., Conclusions: Twenty-two new OATP1B1 inhibitors were identified, a predictive OATP1B1 inhibition in silico model was developed, and successful predictions of clinical DDIs were obtained with OATP1B1.

There is a high need to develop quantitative imaging methods capable of providing detailed brain localization information of several molecular species simultaneously. In addition, extensive information on the effect of the blood-brain barrier on the penetration, distribution and efficacy of neuroactive compounds is required. Thus, we have developed a mass spectrometry imaging method to visualize and quantify the brain distribution of drugs with varying blood-brain barrier permeability. With this approach, we were able to determine blood-brain barrier transport of different drugs and define the drug distribution in very small brain structures (e.g., choroid plexus) due to the high spatial resolution provided. Simultaneously, we investigated the effect of drug-drug interactions by inhibiting the membrane transporter multidrug resistance 1 protein. We propose that the described approach can serve as a valuable analytical tool during the development of neuroactive drugs, as it can provide physiologically relevant information often neglected by traditional imaging technologies. [ABSTRACT FROM AUTHOR]