Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.

Article Details

Citation

Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P

Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.

J Med Chem. 2012 May 24;55(10):4740-63. doi: 10.1021/jm300212s. Epub 2012 May 15.

PubMed ID
22541068 [ View in PubMed
]
Abstract

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.

DrugBank Data that Cites this Article

Drugs
Drug Transporters
DrugTransporterKindOrganismPharmacological ActionActions
AtazanavirSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
AtazanavirSolute carrier organic anion transporter family member 1B3ProteinHumans
Unknown
Inhibitor
Details
AtazanavirSolute carrier organic anion transporter family member 2B1ProteinHumans
Unknown
Inhibitor
Details
BenzbromaroneSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
BenzbromaroneSolute carrier organic anion transporter family member 2B1ProteinHumans
Unknown
Inhibitor
Details
CholecystokininSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Substrate
Inhibitor
Details
CholecystokininSolute carrier organic anion transporter family member 2B1ProteinHumans
Unknown
Inhibitor
Details
ClotrimazoleSolute carrier organic anion transporter family member 1B3ProteinHumans
Unknown
Inducer
Details
DiethylstilbestrolSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
DiethylstilbestrolSolute carrier organic anion transporter family member 2B1ProteinHumans
Unknown
Substrate
Details
DipyridamoleSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
DipyridamoleSolute carrier organic anion transporter family member 1B3ProteinHumans
Unknown
Inhibitor
Details
DipyridamoleSolute carrier organic anion transporter family member 2B1ProteinHumans
Unknown
Inhibitor
Details
ErlotinibSolute carrier organic anion transporter family member 2B1ProteinHumans
Unknown
Inhibitor
Details
GenisteinSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
GenisteinSolute carrier organic anion transporter family member 2B1ProteinHumans
Unknown
Inhibitor
Details
ItraconazoleSolute carrier organic anion transporter family member 2B1ProteinHumans
Unknown
Inhibitor
Details
IvermectinSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
IvermectinSolute carrier organic anion transporter family member 1B3ProteinHumans
Unknown
Inhibitor
Details
LevothyroxineSolute carrier organic anion transporter family member 1A2ProteinHumans
Unknown
Substrate
Details
LevothyroxineSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
LevothyroxineSolute carrier organic anion transporter family member 1B3ProteinHumans
Unknown
Inhibitor
Details
LevothyroxineSolute carrier organic anion transporter family member 1C1ProteinHumans
Unknown
Substrate
Details
LevothyroxineSolute carrier organic anion transporter family member 2B1ProteinHumans
Unknown
Inhibitor
Details
LevothyroxineSolute carrier organic anion transporter family member 4A1ProteinHumans
Unknown
Substrate
Details
NefazodoneSolute carrier organic anion transporter family member 1B3ProteinHumans
Unknown
Inhibitor
Details
NefazodoneSolute carrier organic anion transporter family member 2B1ProteinHumans
Unknown
Inhibitor
Details
NelfinavirSolute carrier organic anion transporter family member 1B3ProteinHumans
Unknown
Inhibitor
Details
NelfinavirSolute carrier organic anion transporter family member 2B1ProteinHumans
Unknown
Inhibitor
Details
NifedipineSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
NovobiocinSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
NovobiocinSolute carrier organic anion transporter family member 1B3ProteinHumans
Unknown
Inhibitor
Details
NovobiocinSolute carrier organic anion transporter family member 2B1ProteinHumans
Unknown
Inhibitor
Details
NystatinSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
NystatinSolute carrier organic anion transporter family member 1B3ProteinHumans
Unknown
Inhibitor
Details
PiroxicamSolute carrier organic anion transporter family member 2B1ProteinHumans
Unknown
Inhibitor
Details
ReserpineSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
ReserpineSolute carrier organic anion transporter family member 2B1ProteinHumans
Unknown
Inhibitor
Details
SilibininSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
SilibininSolute carrier organic anion transporter family member 1B3ProteinHumans
Unknown
Inhibitor
Details
SilibininSolute carrier organic anion transporter family member 2B1ProteinHumans
Unknown
Inhibitor
Details
SincalideSolute carrier organic anion transporter family member 1B3ProteinHumans
Unknown
Substrate
Details
SulfasalazineSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
SulfasalazineSolute carrier organic anion transporter family member 1B3ProteinHumans
Unknown
Inhibitor
Details
SulfasalazineSolute carrier organic anion transporter family member 2B1ProteinHumans
Unknown
Inhibitor
Details
TetracyclineSolute carrier organic anion transporter family member 2B1ProteinHumans
Unknown
Inhibitor
Details
TipranavirSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
TipranavirSolute carrier organic anion transporter family member 1B3ProteinHumans
Unknown
Inhibitor
Details
TipranavirSolute carrier organic anion transporter family member 2B1ProteinHumans
Unknown
Inhibitor
Details
Valproic acidSolute carrier organic anion transporter family member 2B1ProteinHumans
Unknown
Inhibitor
Details
ValspodarSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
ValspodarSolute carrier organic anion transporter family member 1B3ProteinHumans
Unknown
Inhibitor
Details
VincristineSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
VincristineSolute carrier organic anion transporter family member 1B3ProteinHumans
Unknown
Inhibitor
Details
Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
CyclosporineSolute carrier organic anion transporter family member 1B1IC 50 (nM)1400N/AN/ADetails
CyclosporineSolute carrier organic anion transporter family member 1B1Ki (nM)1300N/AN/ADetails
ErlotinibATP-binding cassette sub-family G member 2IC 50 (nM)50000N/AN/ADetails
ErlotinibP-glycoprotein 1IC 50 (nM)26000N/AN/ADetails
RifampicinSolute carrier organic anion transporter family member 1B1Ki (nM)1100N/AN/ADetails
RifampicinSolute carrier organic anion transporter family member 1B1IC 50 (nM)1200N/AN/ADetails
RifampicinSolute carrier organic anion transporter family member 1B3Ki (nM)1400N/AN/ADetails
RifampicinSolute carrier organic anion transporter family member 1B3IC 50 (nM)1500N/AN/ADetails
RifampicinSolute carrier organic anion transporter family member 2B1Ki (nM)63000N/AN/ADetails
RifampicinSolute carrier organic anion transporter family member 2B1IC 50 (nM)65000N/AN/ADetails
RitonavirSolute carrier organic anion transporter family member 1B1Ki (nM)1300N/AN/ADetails
RitonavirSolute carrier organic anion transporter family member 1B1IC 50 (nM)1300N/AN/ADetails