title: Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
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.
authors.affiliation: Department of Pharmacy, Uppsala University, 751 23 Uppsala, Sweden. maria.karlgren@farmaci.uu.se
authors.forename: Maria
authors.initials: M
authors.lastname: Karlgren
authors.forename: Anna
authors.initials: A
authors.lastname: Vildhede
authors.forename: Ulf
authors.initials: U
authors.lastname: Norinder
authors.forename: Jacek R
authors.initials: JR
authors.lastname: Wisniewski
authors.forename: Emi
authors.initials: E
authors.lastname: Kimoto
authors.forename: Yurong
authors.initials: Y
authors.lastname: Lai
authors.forename: Ulf
authors.initials: U
authors.lastname: Haglund
authors.forename: Per
authors.initials: P
authors.lastname: Artursson
mesh_terms: D000069059:Atorvastatin; D001692:Biological Transport / Q000187:drug effects; D004347:Drug Interactions; D004958:Estradiol / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004970:Estrone / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D057809:HEK293 Cells; D006538:Heptanoic Acids / Q000493:pharmacokinetics; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D016018:Least-Squares Analysis; D008099:Liver / Q000378:metabolism*; D027381:Liver-Specific Organic Anion Transporter 1; D008958:Models, Molecular; D015999:Multivariate Analysis; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D011758:Pyrroles / Q000493:pharmacokinetics; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D020033:Protein Isoforms; D011758:Pyrroles; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; C450859:SLCO2B1 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; C025483:estradiol-17 beta-glucuronide; D004970:Estrone; D004958:Estradiol; D000069059:Atorvastatin; C017296:estrone sulfate