In vitro and in silico strategies to identify OATP1B1 inhibitors and predict clinical drug-drug interactions.

Article Details

Citation

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
DrugTransporterKindOrganismPharmacological ActionActions
AmprenavirSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
CandesartanSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
CerivastatinSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Substrate
Inhibitor
Details
DiclofenacSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
DiethylstilbestrolSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
FluvastatinSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Substrate
Inhibitor
Details
IndomethacinSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
KetoconazoleSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
NicardipineSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
OuabainSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Substrate
Inhibitor
Details
PitavastatinSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Substrate
Inhibitor
Details
QuercetinSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
QuinineSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
RosiglitazoneSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
RosuvastatinSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Substrate
Inhibitor
Details
TipranavirSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
ValsartanSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Substrate
Inhibitor
Details
VinblastineSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
Drug Interactions
DrugsInteraction
Ambrisentan
Aminohippuric acid
The excretion of Ambrisentan can be decreased when combined with Aminohippuric acid.
Ambrisentan
Rosiglitazone
The excretion of Ambrisentan can be decreased when combined with Rosiglitazone.
Ambrisentan
Levocarnitine
The excretion of Ambrisentan can be decreased when combined with Levocarnitine.
Ambrisentan
Novobiocin
The excretion of Ambrisentan can be decreased when combined with Novobiocin.
Ambrisentan
Ouabain
The excretion of Ambrisentan can be decreased when combined with Ouabain.
Ambrisentan
Bezafibrate
The excretion of Ambrisentan can be decreased when combined with Bezafibrate.
Ambrisentan
Hyperforin
The excretion of Ambrisentan can be decreased when combined with Hyperforin.
Ambrisentan
Posizolid
The excretion of Ambrisentan can be decreased when combined with Posizolid.
Ambrisentan
Acetylcysteine
The excretion of Ambrisentan can be decreased when combined with Acetylcysteine.
Ambrisentan
Cholecystokinin
The excretion of Ambrisentan can be decreased when combined with Cholecystokinin.
Interactions
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