Investigation of the impact of substrate selection on in vitro organic anion transporting polypeptide 1B1 inhibition profiles for the prediction of drug-drug interactions

The risk assessment of organic anion transporting polypeptide (OATP) 1B1-mediated drug-drug interactions (DDIs) is an indispensable part of drug development. We previously reported that in vitro inhibitory potencies of several inhibitors on OATP1B1 depend on the substrates when prototypical substrat...

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Published in:Drug metabolism and disposition 2015-02, Vol.43 (2), p.235-247
Main Authors: Izumi, Saki, Nozaki, Yoshitane, Maeda, Kazuya, Komori, Takafumi, Takenaka, Osamu, Kusuhara, Hiroyuki, Sugiyama, Yuichi
Format: Article
Language:English
Subjects:
Antihypertensive Agents - metabolism
Binding, Competitive
Biological Transport - drug effects
Cyclohexanes - metabolism
Cyclosporine - pharmacology
Drug Evaluation, Preclinical
Drug Interactions
Estradiol - analogs & derivatives
Estradiol - metabolism
Gemfibrozil - pharmacology
HEK293 Cells
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors - metabolism
Hypoglycemic Agents - metabolism
Kinetics
Membrane Transport Modulators - pharmacology
Models, Biological
Organic Anion Transporters - antagonists & inhibitors
Organic Anion Transporters - genetics
Organic Anion Transporters - metabolism
Phenylalanine - analogs & derivatives
Phenylalanine - metabolism
Recombinant Proteins - metabolism
Rifampin - pharmacology
Solute Carrier Organic Anion Transporter Family Member 1b1
Sulfonamides - metabolism
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Summary:The risk assessment of organic anion transporting polypeptide (OATP) 1B1-mediated drug-drug interactions (DDIs) is an indispensable part of drug development. We previously reported that in vitro inhibitory potencies of several inhibitors on OATP1B1 depend on the substrates when prototypical substrates, estradiol-17β-glucuronide (E₂G), estrone-3-sulfate, and sulfobromophthalein were used as test substrates. The purpose of this study was to comprehensively investigate this substrate-dependent inhibition of OATP1B1 using clinically relevant OATP1B1 inhibitors and substrate drugs. Effects of cyclosporine A (CsA), rifampin, and gemfibrozil on OATP1B1-mediated uptake of 12 substrate drugs were examined in OATP1B1-expressing human embryonic kidney 293 cells. The Ki values (μM) for CsA varied from 0.0771 to 0.486 (6.3-fold), for rifampin from 0.358 to 1.23 (3.4-fold), and for gemfibrozil from 9.65 to 252 (26-fold). Except for the inhibition of torasemide uptake by CsA and that of nateglinide uptake by gemfibrozil, the Ki values were within 2.8-fold of those obtained using E₂G as a substrate. Preincubation potentiated the inhibitory effect of CsA on OATP1B1 with similar magnitude regardless of the substrates. R values calculated based on a static model showed some variation depending on the Ki values determined with various substrates, and such variability could have an impact on the DDI predictions particularly for a weak-to-moderate inhibitor (gemfibrozil). OATP1B1 substrate drugs except for torasemide and nateglinide, or E₂G as a surrogate, is recommended as an in vitro probe in the inhibition experiments, which will help mitigate the risk of false-negative DDI predictions potentially caused by substrate-dependent Ki variation.
ISSN:0090-9556
1521-009X
DOI:10.1124/dmd.114.059105