Interaction of Organic Cations with Organic Anion Transporters

Ahn, Sun Young; Eraly, Satish A.; Tsigelny, Igor F.; Nigám, Sanjay K.

doi:10.1074/jbc.m109.024489

Cited by 58 publications

(57 citation statements)

References 23 publications

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“…Screening with this pharmacophore resulted in several "hits" in the Accelrys small molecule database (not shown). When such screening was used for mOat1 and mOat3, novel inhibitors were identified (Ahn et al, 2009;Wikoff et al, 2011).…”

Section: Resultsmentioning

confidence: 99%

“…8), as described previously elsewhere (Ahn et al, 2009). The following protocol was used: (1) generation of conformational models for each compound, (2) assignment of each molecule as active or inactive (i.e., a principal value of 2 or 0, respectively, in the software), (3) Common Feature Pharmacophore generation using the three-dimensional conformation models in step 1.…”

Section: Pharmacophore Generationmentioning

confidence: 99%

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Organic Anion Transporter 3 Interacts Selectively with Lipophilicβ-Lactam Antibiotics

et al. 2013

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Transporters are major determinants of the disposition of xenobiotics and endogenous chemicals in the body. Organic anion transporter 3 (Oat3) functions in the kidney and brain to remove metabolic waste, toxins, and drugs, and thus transports diverse chemicals. Some b-lactam antibiotics interact with Oat3, and penicillin G exhibits a strong dependence on Oat3 for renal elimination. However, over 80 b-lactams exist, and many have not been assessed for an interaction with Oat3. Moreover, b-lactams continue to receive U.S. Food and Drug Administration approval. This study identified new b-lactam-Oat3 interactions, provided a head-to-head comparison with Oat1, and characterized the physicochemical determinants of affinity for Oat3. Cells expressing mouse Oat3 (mOat3) and Oat1 (mOat1), and human OAT3 (hOAT3) were used to test inhibitors, and high-performance liquid chromatography (HPLC) was used to measure transport. Of 26 b-lactams tested, 12 were clear inhibitors of Oat3, and 14 exhibited poor interactions. Inhibitors exhibited a nearly identical rank-order of potency against mOat3 and hOAT3. Oat1 demonstrated a poor interaction with most b-lactams. The majority of Oat3 inhibitors were substrates, and there were clear physicochemical differences between inhibitors and noninhibitors. That is, inhibitors had nearly 40% fewer hydrogen bond donors (P < 0.001), a lower total polar surface area (P < 0.05), and greater lipophilicity (LogP of inhibitors, +1.41; noninhibitors, 21.54; P < 0.001). Pharmacophore mapping revealed a prohibitive hydrogen bond donor group in noninhibitors adjacent to a hydrophobic moiety that was important for binding to Oat3. These findings indicate that Oat3 recognizes lipophilic b-lactams more readily. Moreover, this study has potential implications for designing b-lactams to avoid renal accumulation or brain efflux via Oat3.

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Section: Resultsmentioning

confidence: 99%

Section: Pharmacophore Generationmentioning

confidence: 99%

Organic Anion Transporter 3 Interacts Selectively with Lipophilicβ-Lactam Antibiotics

et al. 2013

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“…This is the first report of an anionic compound being transported by organic cation transporter OCT1. Regarding organic anion transporters that also belong to solute carrier 22A family as does OCT1, Ahn et al (2009) reported the transport of organic cations by the anion transporter. According to our calculations of partial electric charge in the ELT molecule, the carbon of the carboxyl group and the carbon of the carbonyl group in the pyrazolone ring have a partial positive charge (Supplemental Figure S1).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Hepatic Uptake of Eltrombopag, a Novel Platelet-Increasing Agent

Takeuchi

Sugiura²,

Umeda³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Eltrombopag (ELT) is a novel thrombopoietin receptor agonist for the treatment of idiopathic thrombocytopenic purpura. Previous reports indicate that ELT is mainly eliminated in the liver, although its pharmacokinetic profile has not yet been clarified in detail. The purpose of the present study is to investigate the overall elimination mechanism of ELT. After intravenous administration of ELT to rats, approximately 40% of unchanged ELT was excreted into the bile in 72 h, whereas less than 0.02% of the dose was excreted in urine, indicating that liver is the major elimination organ for ELT. The total clearance was much lower than the hepatic blood flow rate and comparable with hepatic uptake clearance obtained from integration plot analysis. Coadministration of rifampicin, an organic anion transporter inhibitor, reduced both total clearance and hepatic uptake clearance of ELT. These results suggest that hepatic uptake is the rate-limiting process in the overall elimination of ELT. To further characterize the uptake mechanism, uptake of ELT by freshly isolated mouse hepatocytes was examined. The ELT uptake showed concentration and energy dependence and was inhibited by various compounds, including not only organic anions but also organic cations. Hepatic uptake clearance in vivo was reduced by coadministration of an organic cation, tetrapentylammonium. Finally, uptake of ELT was observed in human embryonic kidney 293 cells transfected with human hepatic transporters organic anion-transporting polypeptide (OATP) 1B1 and OATP2B1 and organic cation transporter OCT1. These results suggest that multiple transporters, including organic anion transporters and organic cation transporters, are involved in hepatic ELT uptake.

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“…In addition, newer agents, such as the integrase inhibitor dolutegravir and the novel pharmacoenhancer cobicistat, also block creatinine excretion (34,35). This effect appears to be largely from drug-metabolite interactions due to competition for OCTs, MATEs, and possibly OATs (29,(32)(33)(34)(35).…”

Section: Drugs and Toxinsmentioning

confidence: 99%

“…Drugs such as cimetidine and trimethoprim are examples. OATs, while mainly transporters of organic anions, can also transport some organic cations, including creatinine (32,33). In addition, newer agents, such as the integrase inhibitor dolutegravir and the novel pharmacoenhancer cobicistat, also block creatinine excretion (34,35).…”

Section: Drugs and Toxinsmentioning

confidence: 99%

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

Nigám¹,

Wu²,

Bush³

et al. 2015

Clinical Journal of the American Society of Nephrology

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229

192

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The proximal tubule of the kidney plays a crucial role in the renal handling of drugs (e.g., diuretics), uremic toxins (e.g., indoxyl sulfate), environmental toxins (e.g., mercury, aristolochic acid), metabolites (e.g., uric acid), dietary compounds, and signaling molecules. This process is dependent on many multispecific transporters of the solute carrier (SLC) superfamily, including organic anion transporter (OAT) and organic cation transporter (OCT) subfamilies, and the ATP-binding cassette (ABC) superfamily. We review the basic physiology of these SLC and ABC transporters, many of which are often called drug transporters. With an emphasis on OAT1 (SLC22A6), the closely related OAT3 (SLC22A8), and OCT2 (SLC22A2), we explore the implications of recent in vitro, in vivo, and clinical data pertinent to the kidney. The analysis of murine knockouts has revealed a key role for these transporters in the renal handling not only of drugs and toxins but also of gut microbiome products, as well as liverderived phase 1 and phase 2 metabolites, including putative uremic toxins (among other molecules of metabolic and clinical importance). Functional activity of these transporters (and polymorphisms affecting it) plays a key role in drug handling and nephrotoxicity. These transporters may also play a role in remote sensing and signaling, as part of a versatile small molecule communication network operative throughout the body in normal and diseased states, such as AKI and CKD.

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Interaction of Organic Cations with Organic Anion Transporters

Cited by 58 publications

References 23 publications

Organic Anion Transporter 3 Interacts Selectively with Lipophilicβ-Lactam Antibiotics

Organic Anion Transporter 3 Interacts Selectively with Lipophilicβ-Lactam Antibiotics

Pharmacokinetics and Hepatic Uptake of Eltrombopag, a Novel Platelet-Increasing Agent

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

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