Organic Anion Transporter 2: An Enigmatic Human Solute Carrier

Shen, Hong; Lai, Yurong; Rodrigues, A. David

doi:10.1124/dmd.116.072264

Cited by 68 publications

(49 citation statements)

References 90 publications

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“…For OAT2, interesting results have recently been reported. For details on OAT2, the reader may refer to an excellent, recent review (Shen et al, 2017b). Ciarimboli et al (2012) found significant OAT2-mediated creatinine uptake.…”

Section: Biomarkers For Function Of Renal Cation Transporters (Orgmentioning

confidence: 99%

“…6b-Hydroxycortisol is not transported by OAT1 and P-glycoprotein (Imamura et al, 2013) (Table 2). 6b-Hydroxycortisol is also a substrate of MATE1 and, with a low transport rate, of Tamai et al, 1998;Yabuuchi et al, 1999;Enomoto et al, 2002;Tanihara et al, 2007;Lancaster et al, 2010;Palmieri, 2013;Kato et al, 2014;Wu et al, 2015;Giangregorio et Urakami et al, 2004;Masuda et al, 2006;Tanihara et al, 2007;Imamura et al, 2011;Ciarimboli et al, 2012;Lepist et al, 2014;Shen et al, 2015Shen et al, , 2017bChu et al, 2016;Mathialagan et al, 2017 Dopamine c Catecholamine, neurotransmitter…”

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confidence: 99%

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Biomarkers for In Vivo Assessment of Transporter Function

Müller¹,

Sharma²,

König³

et al. 2018

Pharmacol Rev

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Drug-drug interactions are a major concern not only during clinical practice, but also in drug development. Due to limitations of in vitro-in vivo predictions of transporter-mediated drug-drug interactions, multiple clinical Phase I drug-drug interaction studies may become necessary for a new molecular entity to assess potential drug interaction liabilities. This is a resource-intensive process and exposes study participants, who frequently are healthy volunteers without benefit from study treatment, to the potential risks of a new drug in development. Therefore, there is currently a major interest in new approaches for better prediction of transporter-mediated drug-drug interactions. In particular, researchers in the field attempt to identify endogenous compounds as biomarkers for transporter function, such as hexadecanedioate, tetradecanedioate, coproporphyrins I and III, or glycochenodeoxycholate sulfate for hepatic uptake via organic anion transporting polypeptide 1B or N-methylnicotinamide for multidrug and toxin extrusion protein-mediated renal secretion. We summarize in this review the currently proposed biomarkers and potential limitations of the substances identified to date. Moreover, we suggest criteria based on current experiences, which may be used to assess the suitability of a biomarker for transporter function. Finally, further alternatives and supplemental approaches to classic drug-drug interaction studies are discussed.

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Section: Biomarkers For Function Of Renal Cation Transporters (Orgmentioning

confidence: 99%

mentioning

confidence: 99%

Biomarkers for In Vivo Assessment of Transporter Function

Müller¹,

Sharma²,

König³

et al. 2018

Pharmacol Rev

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“…Emphasis has been given to hepatic uptake clearance mediated by organic anion transporting polypetides (OATPs), where many high-molecular-weight acids/zwitterions (ECCS class 1B/3B) are shown to be substrates (Giacomini et al, 2010;Shitara et al, 2013;Varma et al, 2015Varma et al, , 2017b. OAT2, a member of solute carrier 22A (SLC22A7), is expressed in the liver and kidney and is known to transport several xenobiotics and endogenous compounds (e.g., creatinine and cGMP) (Lepist et al, 2014;Shen et al, 2017). Although protein abundance of OAT2 in the human liver is relatively similar to that of other major uptake transporters, such as OATP1B, Na1-taurocholate cotransporting polypeptide, and organic cation transporter (OCT)1 (Nakamura et al, 2016;Vildhede et al, 2018), little is known about its role in the clinical pharmacokinetics of drugs (Shen et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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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“…In agreement, PAH showed no competition with uptake of indomethacin, cGMP, or cAMP. Earlier studies claimed that PAH was a hOAT2 substrate but a recent review questions this (Shen, Lai, & Rodrigues, ).…”

Section: Discussionmentioning

confidence: 99%

The role of OAT2 (SLC22A7) in the cyclic nucleotide biokinetics of human erythrocytes

Sager

Smaglyukova

Fuskevaag

2018

Journal Cellular Physiology

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The present study was conducted to characterise the transporter(s) responsible for the uptake of cyclic nucleotides to human erythrocytes. Western blotting showed that hRBC expressed OAT2 (SLC22A7), but detection of OAT1 (SLC22A6), or OAT3 (SLC22A8) was not possible. Intact hRBC were employed to clarify the simultaneous cyclic nucleotide egression and uptake. Both these opposing processes were studied. The Km‐values for high affinity efflux was 3.5 ± 0.1 and 39.4 ± 5.7 μM for cGMP and cAMP, respectively. The respective values for low affinity efflux were 212 ± 11 and 339 ± 42 μM. The uptake was characterised with apparently low affinity and similar Km‐values for cGMP (2.2 mM) and cAMP (0.89 mM). Using an iterative approach in order to balance uptake with efflux, the predicted real Km‐values for uptake were 100–200 μM for cGMP and 50–150 μM for cAMP. The established OAT2‐substrate indomethacin showed a competitive interaction with cyclic nucleotide uptake. Creatinine, also an OAT2 substrate, showed saturable uptake with a Km of 854 ± 98 μM. Unexpectedly, co‐incubation with cyclic nucleotides showed an uncompetitive inhibition. The observed Km‐values were 399 ± 44 and 259 ± 30 μM for creatinine, in the presence of cGMP and cAMP, respectively. Finally, the OAT1‐substrate para‐aminohippurate (PAH) showed some uptake (Km‐value of 2.0 ± 0.4 mM) but did not interact with cyclic nucleotide or indomethacin transport.

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Organic Anion Transporter 2: An Enigmatic Human Solute Carrier

Cited by 68 publications

References 90 publications

Biomarkers for In Vivo Assessment of Transporter Function

Biomarkers for In Vivo Assessment of Transporter Function

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

The role of OAT2 (SLC22A7) in the cyclic nucleotide biokinetics of human erythrocytes

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