In Vitro and In Silico Strategies to Identify OATP1B1 Inhibitors and Predict Clinical Drug–Drug Interactions

Abstract

PurposeTo establish in vitro and in silico models that predict clinical drug–drug interactions (DDIs) with the OATP1B1 (SLCO1B1) transporter.MethodsThe 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.ResultsSixty-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.ConclusionsTwenty-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.

Hepatic Uptake of Atorvastatin: Influence of Variability in Transporter Expression on Uptake Clearance and Drug-Drug Interactions

“…The inserted sequence was verified by DNA sequencing analysis. Human embryonic kidney (HEK) Flp-In-293 cells (Invitrogen) were transfected with the constructed NTCP-pcDNA5/FRT expression vector and further selected using hygromycin B (Invitrogen), as previously described elsewhere (Karlgren et al, 2012a).…”

“…Mock-transfected HEK Flp-In-293 cells and cells stably expressing NTCP or either of the three OATP transporters [established and characterized by Karlgren et al (2012a,b)] were cultivated as described elsewhere (Karlgren et al, 2012a). Passages between 10 and 30 were used throughout the study.…”

Clearance Prediction of HIV Protease Inhibitors in Man: Role of Hepatic Uptake

“…14,16,17,33 Consistently, OATP inhibition explained the marked increase in the area under the plasma concentration-time curve of the OATP1B1 substrates bosentan and rosuvastatin, when co-administered with the combination of lopinavir and ritonavir in healthy volunteers. 34,35 In addition to the OATP1B inhibitory potential of HIV PI, several studies revealed that these drugs also show affinity for OATP1B isoforms as substrates.…”

“…12,13 Several studies have illustrated that HIV PI inhibit the in vitro cellular uptake of OATP1B probe substrates like estradiol-17β-D-glucuronide, CGamF and sodium fluorescein. [14][15][16][17] Moreover, it has been suggested that inhibition of these membrane transporters contributes to clinically important antiretroviral drug-drug interactions, for example with cerivastatin and atorvastatin. 18 While these examples certainly illustrate the clinical relevance of OATP modulation by HIV PI, the concept of meaningful OATPmediated transport of HIV PI remains controversial.…”

Effect of OATP-binding on the prediction of biliary excretion

“…The OATP subfamilies, OATP1B1, OATP1B3 and OATP2B1 were included in the dataset. A total of 142 compounds in this dataset was from an earlier investigation (Karlgren et al 2012b), which was then expanded to include compounds known to interact with OATPs or CYP enzymes (Karlgren et al, 2012a). The compounds were from the chemical space of oral drugs (Karlgren et al, 2012a).…”