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

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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

Nystatin

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Atazanavir	Solute carrier organic anion transporter family member 1B1	Protein	Humans	Unknown	Inhibitor	Details
Atazanavir	Solute carrier organic anion transporter family member 1B3	Protein	Humans	Unknown	Inhibitor	Details
Atazanavir	Solute carrier organic anion transporter family member 2B1	Protein	Humans	Unknown	Inhibitor	Details
Benzbromarone	Solute carrier organic anion transporter family member 1B1	Protein	Humans	Unknown	Inhibitor	Details
Benzbromarone	Solute carrier organic anion transporter family member 2B1	Protein	Humans	Unknown	Inhibitor	Details
Cholecystokinin	Solute carrier organic anion transporter family member 1B1	Protein	Humans	Unknown	Substrate Inhibitor	Details
Cholecystokinin	Solute carrier organic anion transporter family member 2B1	Protein	Humans	Unknown	Inhibitor	Details
Clotrimazole	Solute carrier organic anion transporter family member 1B3	Protein	Humans	Unknown	Inducer	Details
Diethylstilbestrol	Solute carrier organic anion transporter family member 1B1	Protein	Humans	Unknown	Inhibitor	Details
Diethylstilbestrol	Solute carrier organic anion transporter family member 2B1	Protein	Humans	Unknown	Substrate	Details
Dipyridamole	Solute carrier organic anion transporter family member 1B1	Protein	Humans	Unknown	Inhibitor	Details
Dipyridamole	Solute carrier organic anion transporter family member 1B3	Protein	Humans	Unknown	Inhibitor	Details
Dipyridamole	Solute carrier organic anion transporter family member 2B1	Protein	Humans	Unknown	Inhibitor	Details
Erlotinib	Solute carrier organic anion transporter family member 2B1	Protein	Humans	Unknown	Inhibitor	Details
Genistein	Solute carrier organic anion transporter family member 1B1	Protein	Humans	Unknown	Inhibitor	Details
Genistein	Solute carrier organic anion transporter family member 2B1	Protein	Humans	Unknown	Inhibitor	Details
Itraconazole	Solute carrier organic anion transporter family member 2B1	Protein	Humans	Unknown	Inhibitor	Details
Ivermectin	Solute carrier organic anion transporter family member 1B1	Protein	Humans	Unknown	Inhibitor	Details
Ivermectin	Solute carrier organic anion transporter family member 1B3	Protein	Humans	Unknown	Inhibitor	Details
Levothyroxine	Solute carrier organic anion transporter family member 1A2	Protein	Humans	Unknown	Substrate	Details
Levothyroxine	Solute carrier organic anion transporter family member 1B1	Protein	Humans	Unknown	Inhibitor	Details
Levothyroxine	Solute carrier organic anion transporter family member 1B3	Protein	Humans	Unknown	Inhibitor	Details
Levothyroxine	Solute carrier organic anion transporter family member 1C1	Protein	Humans	Unknown	Substrate	Details
Levothyroxine	Solute carrier organic anion transporter family member 2B1	Protein	Humans	Unknown	Inhibitor	Details
Levothyroxine	Solute carrier organic anion transporter family member 4A1	Protein	Humans	Unknown	Substrate	Details
Nefazodone	Solute carrier organic anion transporter family member 1B3	Protein	Humans	Unknown	Inhibitor	Details
Nefazodone	Solute carrier organic anion transporter family member 2B1	Protein	Humans	Unknown	Inhibitor	Details
Nelfinavir	Solute carrier organic anion transporter family member 1B3	Protein	Humans	No	Inhibitor	Details
Nelfinavir	Solute carrier organic anion transporter family member 2B1	Protein	Humans	No	Inhibitor	Details
Nifedipine	Solute carrier organic anion transporter family member 1B1	Protein	Humans	Unknown	Inhibitor	Details
Novobiocin	Solute carrier organic anion transporter family member 1B1	Protein	Humans	Unknown	Inhibitor	Details
Novobiocin	Solute carrier organic anion transporter family member 1B3	Protein	Humans	Unknown	Inhibitor	Details
Novobiocin	Solute carrier organic anion transporter family member 2B1	Protein	Humans	Unknown	Inhibitor	Details
Nystatin	Solute carrier organic anion transporter family member 1B1	Protein	Humans	Unknown	Inhibitor	Details
Nystatin	Solute carrier organic anion transporter family member 1B3	Protein	Humans	Unknown	Inhibitor	Details
Piroxicam	Solute carrier organic anion transporter family member 2B1	Protein	Humans	Unknown	Inhibitor	Details
Reserpine	Solute carrier organic anion transporter family member 1B1	Protein	Humans	Unknown	Inhibitor	Details
Reserpine	Solute carrier organic anion transporter family member 2B1	Protein	Humans	Unknown	Inhibitor	Details
Silibinin	Solute carrier organic anion transporter family member 1B1	Protein	Humans	Unknown	Inhibitor	Details
Silibinin	Solute carrier organic anion transporter family member 1B3	Protein	Humans	Unknown	Inhibitor	Details
Silibinin	Solute carrier organic anion transporter family member 2B1	Protein	Humans	Unknown	Inhibitor	Details
Sincalide	Solute carrier organic anion transporter family member 1B3	Protein	Humans	Unknown	Substrate	Details
Sulfasalazine	Solute carrier organic anion transporter family member 1B1	Protein	Humans	No	Inhibitor	Details
Sulfasalazine	Solute carrier organic anion transporter family member 1B3	Protein	Humans	No	Inhibitor	Details
Sulfasalazine	Solute carrier organic anion transporter family member 2B1	Protein	Humans	No	Inhibitor	Details
Tetracycline	Solute carrier organic anion transporter family member 2B1	Protein	Humans	Unknown	Inhibitor	Details
Tipranavir	Solute carrier organic anion transporter family member 1B1	Protein	Humans	Unknown	Inhibitor	Details
Tipranavir	Solute carrier organic anion transporter family member 1B3	Protein	Humans	Unknown	Inhibitor	Details
Tipranavir	Solute carrier organic anion transporter family member 2B1	Protein	Humans	Unknown	Inhibitor	Details
Valproic acid	Solute carrier organic anion transporter family member 2B1	Protein	Humans	Unknown	Inhibitor	Details
Valspodar	Solute carrier organic anion transporter family member 1B1	Protein	Humans	Unknown	Inhibitor	Details
Valspodar	Solute carrier organic anion transporter family member 1B3	Protein	Humans	Unknown	Inhibitor	Details
Vincristine	Solute carrier organic anion transporter family member 1B1	Protein	Humans	Unknown	Inhibitor	Details
Vincristine	Solute carrier organic anion transporter family member 1B3	Protein	Humans	Unknown	Inhibitor	Details

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Cyclosporine	Solute carrier organic anion transporter family member 1B1	IC 50 (nM)	1400	N/A	N/A	Details
Cyclosporine	Solute carrier organic anion transporter family member 1B1	Ki (nM)	1300	N/A	N/A	Details
Erlotinib	ATP-binding cassette sub-family G member 2	IC 50 (nM)	50000	N/A	N/A	Details
Erlotinib	P-glycoprotein 1	IC 50 (nM)	26000	N/A	N/A	Details
Rifampicin	Solute carrier organic anion transporter family member 1B1	Ki (nM)	1100	N/A	N/A	Details
Rifampicin	Solute carrier organic anion transporter family member 1B1	IC 50 (nM)	1200	N/A	N/A	Details
Rifampicin	Solute carrier organic anion transporter family member 1B3	Ki (nM)	1400	N/A	N/A	Details
Rifampicin	Solute carrier organic anion transporter family member 1B3	IC 50 (nM)	1500	N/A	N/A	Details
Rifampicin	Solute carrier organic anion transporter family member 2B1	Ki (nM)	63000	N/A	N/A	Details
Rifampicin	Solute carrier organic anion transporter family member 2B1	IC 50 (nM)	65000	N/A	N/A	Details
Ritonavir	Solute carrier organic anion transporter family member 1B1	Ki (nM)	1300	N/A	N/A	Details
Ritonavir	Solute carrier organic anion transporter family member 1B1	IC 50 (nM)	1300	N/A	N/A	Details