In vitro and in silico strategies to identify OATP1B1 inhibitors and predict clinical drug-drug interactions.
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Karlgren M, Ahlin G, Bergstrom CA, Svensson R, Palm J, Artursson P
In vitro and in silico strategies to identify OATP1B1 inhibitors and predict clinical drug-drug interactions.
Pharm Res. 2012 Feb;29(2):411-26. doi: 10.1007/s11095-011-0564-9. Epub 2011 Aug 23.
- PubMed ID
- 21861202 [ View in PubMed]
- Abstract
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 muM. 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.
DrugBank Data that Cites this Article
- Drug Transporters
- Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareAmbrisentanAminohippuric acid The excretion of Ambrisentan can be decreased when combined with Aminohippuric acid. AmbrisentanRosiglitazone The excretion of Ambrisentan can be decreased when combined with Rosiglitazone. AmbrisentanLevocarnitine The excretion of Ambrisentan can be decreased when combined with Levocarnitine. AmbrisentanNovobiocin The excretion of Ambrisentan can be decreased when combined with Novobiocin. AmbrisentanOuabain The excretion of Ambrisentan can be decreased when combined with Ouabain.