Contribution of organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 to hepatic uptake of nateglinide, and the prediction of drug–drug interactions via these transporters

Takanohashi, Toshiyuki; Kubo, Satoru; Arisaka, Harumi; Shinkai, Kenkichi; Ubukata, Kazuyuki

doi:10.1111/j.2042-7158.2011.01389.x

Cited by 14 publications

(7 citation statements)

References 30 publications

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“…We observed a minimal overlap in the substrate specificity for OAT2 versus OATP1B1, which is in general agreement that OATPs preferentially accept high-MW (.400 Da) acids/zwitterions (class 1B) as substrates (Varma et al, 2012a). Of the four OATP1B1 substrates identified in the ECCS 1A space, nateglinide and fluorescein were previously reported to be OATPs substrates (De Bruyn et al, 2011;Takanohashi et al, 2012;Izumi et al, 2016), whereas this is the first report suggesting that bromfenac, an nonsteroidal anti-inflammatory drugs for ocular inflammation, and entacapone, an catechol-O-methyltransferase inhibitor used in Parkinson disease, involve OATP1B1-mediated hepatic uptake clearance. Clinical drug-drug interaction studies with OATP inhibitors rifampicin and cyclosporine may be helpful to further define uptake-determined clearance in these cases.…”

Section: Oat2-mediated Hepatic Uptake Clearancesupporting

confidence: 85%

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Organic Anion Transporter 2–Mediated Hepatic Uptake Contributes to the Clearance of High-Permeability–Low-Molecular-Weight Acid and Zwitterion Drugs: Evaluation Using 25 Drugs

Kimoto

Mathialagan

Tylaska

et al. 2018

J Pharmacol Exp Ther

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High-permeability-low-molecular-weight acids/zwitterions [i.e., extended clearance classification system class 1A (ECCS 1A) drugs] are considered to be cleared by metabolism with a minimal role of membrane transporters in their hepatic clearance. However, a marked disconnect in the in vitro-in vivo (IVIV) translation of hepatic clearance is often noted for these drugs. Metabolic rates measured using human liver microsomes and primary hepatocytes tend to underpredict. Here, we evaluated the role of organic anion transporter 2 (OAT2)-mediated hepatic uptake in the clearance of ECCS 1A drugs. For a set of 25 ECCS 1A drugs, in vitro transport activity was assessed using transporter-transfected cells and primary human hepatocytes. All but two drugs showed substrate affinity to OAT2, whereas four (bromfenac, entacapone, fluorescein, and nateglinide) also showed OATP1B1 activity in transfected cells. Most of these drugs (21 of 25) showed active uptake by plated human hepatocytes, with rifamycin SV (pan-transporter inhibitor) reducing the uptake by about 25%-95%. Metabolic turnover was estimated for 19 drugs after a few showed no measurable substrate depletion in liver microsomal incubations. IVIV extrapolation using in vitro data was evaluated to project human hepatic clearance of OAT2-alone substrates considering 1) uptake transport only, 2) metabolism only, and 3) transporter-enzyme interplay (extended clearance model). The transporter-enzyme interplay approach achieved improved prediction accuracy (average fold error = 1.9 and bias = 0.93) compared with the other two approaches. In conclusion, this study provides functional evidence for the role of OAT2-mediated hepatic uptake in determining the pharmacokinetics of several clinically important ECCS 1A drugs.

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Section: Oat2-mediated Hepatic Uptake Clearancesupporting

confidence: 85%

“…OAT2-Mediated Hepatic Uptake Clearance nateglinide were previously shown to be OATP1B1 substrates (De Bruyn et al, 2011;Takanohashi et al, 2012;Izumi et al, 2016). For all the other compounds, the noted transporter substrate affinity was previously unknown to our best knowledge.…”

Section: Resultsmentioning

confidence: 96%

Organic Anion Transporter 2–Mediated Hepatic Uptake Contributes to the Clearance of High-Permeability–Low-Molecular-Weight Acid and Zwitterion Drugs: Evaluation Using 25 Drugs

Kimoto

Mathialagan

Tylaska

et al. 2018

J Pharmacol Exp Ther

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“…An elementary consequence of standard enzyme kinetics is that molecules using the same protein may compete with or inhibit each other, in this case each other's transport. This is a simply vast topic, so (notwithstanding earlier critiques of summarizing via the enormous review literature), we here simply point out several useful and recent reviews (from the last 3 years only) that describe in detail the many named and genetically identified transporters that are involved in DDI (Han, 2011; Kido et al, 2011; Klatt et al, 2011; König, 2011; Maeda et al, 2011; Marzolini et al, 2011; Müller and Fromm, 2011; Riches et al, 2011; Shitara, 2011; Zhang et al, 2011b; Bi et al, 2012; Elsby et al, 2012; Feng et al, 2012, 2013, 2014; Fromm, 2012; Grandvuinet et al, 2012; Karlgren et al, 2012; Keogh, 2012; Lepist and Ray, 2012; Nies et al, 2012; Sissung et al, 2012; Sprowl and Sparreboom, 2012, 2014; Takanohashi et al, 2012; Varma et al, 2012; Yeo et al, 2012, 2013; Yoshida et al, 2012, 2013; Kis et al, 2013; König et al, 2013; Maeda and Sugiyama, 2013; Sugiyama and Steffansen, 2013; Tang et al, 2013; Zamek-Gliszczynski et al, 2013; Goswami et al, 2014; Tannenbaum and Sheehan, 2014; Vildhede et al, 2014). We are not aware of any papers that showed such DDI based on any measured competition for transport via the phospholipid bilayer.…”

Section: Some Further Areas Where the Hypothesis Of Dominant Transpormentioning

confidence: 99%

How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion

Kell¹,

Oliver²

2014

Front. Pharmacol.

146

169

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One approach to experimental science involves creating hypotheses, then testing them by varying one or more independent variables, and assessing the effects of this variation on the processes of interest. We use this strategy to compare the intellectual status and available evidence for two models or views of mechanisms of transmembrane drug transport into intact biological cells. One (BDII) asserts that lipoidal phospholipid Bilayer Diffusion Is Important, while a second (PBIN) proposes that in normal intact cells Phospholipid Bilayer diffusion Is Negligible (i.e., may be neglected quantitatively), because evolution selected against it, and with transmembrane drug transport being effected by genetically encoded proteinaceous carriers or pores, whose “natural” biological roles, and substrates are based in intermediary metabolism. Despite a recent review elsewhere, we can find no evidence able to support BDII as we can find no experiments in intact cells in which phospholipid bilayer diffusion was either varied independently or measured directly (although there are many papers where it was inferred by seeing a covariation of other dependent variables). By contrast, we find an abundance of evidence showing cases in which changes in the activities of named and genetically identified transporters led to measurable changes in the rate or extent of drug uptake. PBIN also has considerable predictive power, and accounts readily for the large differences in drug uptake between tissues, cells and species, in accounting for the metabolite-likeness of marketed drugs, in pharmacogenomics, and in providing a straightforward explanation for the late-stage appearance of toxicity and of lack of efficacy during drug discovery programmes despite macroscopically adequate pharmacokinetics. Consequently, the view that Phospholipid Bilayer diffusion Is Negligible (PBIN) provides a starting hypothesis for assessing cellular drug uptake that is much better supported by the available evidence, and is both more productive and more predictive.

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“…Currently, various clinically used drugs including statins (Sharma et al, 2012), angiotensin II receptor blockers (Yamashiro et al, 2006), endothelin receptor antagonists , antidiabetics (Takanohashi et al, 2012), and diuretics (Werner et al, 2010) are known as OATP1B1 substrates. These clinically used OATP1B1 substrate drugs, in addition to prototypical substrates, could also serve as in vitro probe substrates because of their clinical relevance.…”

Section: Introductionmentioning

confidence: 99%

Investigation of the Impact of Substrate Selection on In Vitro Organic Anion Transporting Polypeptide 1B1 Inhibition Profiles for the Prediction of Drug-Drug Interactions

Izumi¹,

Nozaki²,

Maeda³

et al. 2014

Drug Metab Dispos

129

139

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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-17b-glucuronide (E 2 G), 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 K i values (mM) 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 K i values were within 2.8-fold of those obtained using E 2 G 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 K i 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 E 2 G 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 substratedependent K i variation.

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Contribution of organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 to hepatic uptake of nateglinide, and the prediction of drug–drug interactions via these transporters

Abstract: OATP1B1 and OATP1B3 may have contributed to the hepatic uptake of nateglinide, but the possibility of drug-drug interactions appeared to be low.

Cited by 14 publications

References 30 publications

Organic Anion Transporter 2–Mediated Hepatic Uptake Contributes to the Clearance of High-Permeability–Low-Molecular-Weight Acid and Zwitterion Drugs: Evaluation Using 25 Drugs

Organic Anion Transporter 2–Mediated Hepatic Uptake Contributes to the Clearance of High-Permeability–Low-Molecular-Weight Acid and Zwitterion Drugs: Evaluation Using 25 Drugs

How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion

Investigation of the Impact of Substrate Selection on In Vitro Organic Anion Transporting Polypeptide 1B1 Inhibition Profiles for the Prediction of Drug-Drug Interactions

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