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

Maria Karlgren; Anna Vildhede; Ulf Norinder; Jacek R Wisniewski; Emi Kimoto; Yurong Lai; Ulf Haglund; Per Artursson

doi:10.1021/jm300212s

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.

Authors

Maria Karlgren¹, Anna Vildhede, Ulf Norinder, Jacek R Wisniewski, Emi Kimoto, Yurong Lai, Ulf Haglund, Per Artursson

Affiliation

¹ Department of Pharmacy, Uppsala University, 751 23 Uppsala, Sweden. maria.karlgren@farmaci.uu.se

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Atorvastatin
Biological Transport / drug effects
Drug Interactions*
Estradiol / analogs & derivatives
Estradiol / pharmacokinetics
Estrone / analogs & derivatives
Estrone / pharmacokinetics
HEK293 Cells
Heptanoic Acids / pharmacokinetics
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacokinetics
In Vitro Techniques
Least-Squares Analysis
Liver / metabolism*
Liver-Specific Organic Anion Transporter 1
Models, Molecular*
Multivariate Analysis
Organic Anion Transporters / antagonists & inhibitors*
Organic Anion Transporters / genetics
Organic Anion Transporters / metabolism
Organic Anion Transporters, Sodium-Independent / antagonists & inhibitors*
Organic Anion Transporters, Sodium-Independent / genetics
Organic Anion Transporters, Sodium-Independent / metabolism
Protein Isoforms / antagonists & inhibitors
Protein Isoforms / metabolism
Pyrroles / pharmacokinetics
Solute Carrier Organic Anion Transporter Family Member 1B3
Structure-Activity Relationship
Transfection

Substances

Heptanoic Acids
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Liver-Specific Organic Anion Transporter 1
Organic Anion Transporters
Organic Anion Transporters, Sodium-Independent
Protein Isoforms
Pyrroles
SLCO1B1 protein, human
SLCO1B3 protein, human
SLCO2B1 protein, human
Solute Carrier Organic Anion Transporter Family Member 1B3
estradiol-17 beta-glucuronide
Estrone
Estradiol
Atorvastatin
estrone sulfate