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Primacyt Transporter Assays - ADME - Toxicology Assays


OAT - Organic Anion Transporter


Start your Project and why you should contact us.
Primacyt is a functional precision service organization in the field of OATs. We offer a broad portfolio of transporter assays for OATs. We support industry, research organizations and government in the field of in vitro studies related to drug interaction from the beginning of your projects until preclinical completion.

We are highly committed to offering additional categories of laboratory services and analytical topics as a commitment to the continuous expansion of our leading position in the industry. We are your partner and the partner of your clients in the education, training, and development of testing protocols. We also offer permanent routine lab services as a customized approach and service. You are in a position to open up additional revenue streams for your organization and partners.

Our partners contact us for getting advice on many questions and facts related to

  • OCT1, OCT2, OCT3 Transporter, SLC22A
  • Organic Cation Transporter, Organic Drug Transporter, Organic Drug Transporter Inhibitors

We are your partner when it comes to questions about drug-drug interaction or related lab service work for drug development.


OATs in 30 seconds.
Transporters are proteins carrying endogenous compounds or xenobiotics across biological membranes. We differentiate between uptake or efflux proteins, pending on the transport direction in or out of the cells. Removing molecules out of a cell need ATP-dependent efflux pumps, whereas for the transport in the reverse direction uptake transporter for the import of ions and nutrients, for example, glucose is expressed in the cell membrane.

Transporters are needed for:
  • Regulation of bioavailability
  • Transportation of drug targets
  • Elimination of toxins
  • Defeat of resistance

Organic anion transporters can be arranged in OATs (organic anion transporters), OATPs (organic anion transporting polypeptides) and multiple drug resistance-associated proteins MRPs.

We distinguish between the isoforms OAT1 to OAT5.

OATs are members of the solute carrier family SLC, in detail to the SLCO gene subfamily. SLCs are relevant for the maintenance of homeostasis.

Organic Anion Transporters are ionic agents inhibiting low passive membrane permeability, resulting in reduced bioavailability.

OATs have ubiquitously expressed all organs, including kidney, liver, and intestine. The function of OATs is renal clearance. Substrates are transported from the bloodstream into the kidney. OAT1 is involved in the renal elimination of these compounds and metabolites. OAT2 is also expressed in the liver to a greater extent, whereas at a lower level they are expressed in the brain, muscles, eye, placenta and the basolateral membrane of proximal tubular cells of the kidney.


The Transporters are membrane transport proteins for the transport of organic anions across the sinusoidal membrane of cells. They are present in the lipid bilayer of the cell membrane. Oats serve as transporters for the removal of xenobiotics. We find OAT1 and OAT2 on the basolateral membrane, whereas OAT4 is localized on the apical membrane.

OATS organic anion transporters are hepatic transporters for uptake of drugs and bile salt on the basolateral membrane. They are polyspecific and interact with a variety of organic anion drugs, such as antiviral drugs, antitumor drugs, anti-inflammatory drugs, and enzyme inhibitors.

Project Schedule - How we can work together
Primacyt Cell Culture GmbH provides cell culture solutions for biomedical and cell biology research. PRIMACYT is focused on in-vitro-technologies, certified according to GLP. Our focus is in the fields of hepatocytes, subcellular fractions, skin tissues, cell culture media, hydrogel 3D cultures, and collagen products. We provide solutions for human and animal research.

According to the needs of your organization, we can agree on a mutual confidentiality agreement. We discuss your project needs and send you the first offer with the contractually relevant project details.

Our past cooperation partners foresee different needs for the formal contracts the parties need to agree upon. As typically our joint projects are relatively uncomplicated relative to drug discovery projects, we suggest a simple, fast-track approach to save your time for the benefit of your projects.

We are in a position to provide umbrella or master agreement type contract versions, followed by a project amendment or packaging everything in a single document. We are prepared to send you templates for such agreements including material transfer agreements if needed. Contract languages can be English or German for you as a commercial or government / academic entity.

We always suggest to exchange data through cloud mechanisms and to cooperate by life video or telephone conferences also in other languages including Chinese.


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OAT1
OAT1, the organic anion transporter 1 is known as solute carrier family 22 member 6 (SLC22A6). The protein is encoded by the SLC22A6 gene in humans. OAT1 are expressed in the brain, placenta, eyes, smooth muscles, and the basolateral membrane of proximal tubular cells of the kidneys.

Major R&D activities comprise the organic anion transporter 1 topic as with issues about protein expression, acid, and OAT1 in combination with OAT3. The second key focus is on drug transporters (OAT1, OAT) hepatic drug transporters and about clinically essential drugs. OAT1 plays a central role in renal organic anion transport.

Besides, OAT1 and OAT3 can handle many endogenous metabolites, including some uremic toxins or retention solutes. Kidney proximal tubule (PT) transporters of uremic toxins and solutes include the two transporters OAT1 and OAT3. They are essential for the regulation of the uremic solutes and support their centrality in an independent and synergistic regulation of the uremic metabolism.

In conjunction with OAT3, OAT1 mediates the uptake of a wide range of small and hydrophilic organic anions. Uptake ic from plasma into the cytoplasm of the proximal tubular cells of the kidneys. The substrates are transported into the lumen of the nephrons of the kidneys for excretion. Homologs to OAT1 are known in rats, mice, rabbits, pigs, and flounders.

OAT1 is an organic anion exchanger. When one molecule of an organic anion is transported into a cell, one molecule of an endogenous dicarboxylic acid is transported out in the opposite direction.

The removal of endogenous dicarboxylic acid, OAT1-positive cells bears the risk of depleting too many dicarboxylates. When the supply of endogenous dicarboxylates is exhausted, the OAT1 transporter cannot longer function. For the balance of loss of dicarboxylates, OAT1-positive cells also express the sodium-dicarboxylate cotransporter NaDC3, replenishing dicarboxylates back into the OAT1-positive cell. This means that Sodium supply is needed for replenishment. However a sodium gradient across the cell membrane is mandatory; otherwise, the NaDC3 cotransporter will not function. As a result, again intra-cellular dicarboxylates are depleted, and the OAT1 transporter function is yet not active.
OAT2
The organic anion transporters OATs (OAT1 to OAT6) are members of the solute carrier family (SLC) 22A with 12 transmembrane domains and are mainly expressed in the apical or basolateral membrane of the renal proximal tubules, the site of active drug secretion. OATs are also expressed in the liver, kidney and other organs like the brain, placenta, and testis. The encoded protein is involved in the sodium-independent transport and excretion of organic anions, some of which are potentially toxic and is an integral membrane protein.

Because it serves to take substrates from the bloodstream into the kidney and liver, OAT2 can mediate the elimination of these compounds. OAT2 is emerging as an essential drug transporter because of its expression in both the liver and kidney, two major eliminating organs, and its ability to transport not only a wide variety of xenobiotics but also numerous physiologically important endogenous compounds.

However, OAT2 has received less attention when compared to other OATs and solute carriers (SLCs) like organic cation transporters, sodium-dependent taurocholate co-transporting polypeptide, multidrug and toxin extrusion proteins, and organic anion-transporting polypeptides.

OAT2 is recognized as rapidly evolving, with numerous publications regarding the transport mechanism, tissue distribution, and transport of creatinine and cGMP, two important endogenous compounds of OAT2.

Human OAT2 is acting as an organic anion/dicarboxylate exchanger, OAT2 mediates transport of endogenous molecules including dicarboxylic acids, nucleotides and uric acid, lipid hormones and mediators, and creatinine, as well as xenobiotics such as anticancer drugs, antivirals, and antibiotics.

Many xenobiotics increase serum creatinine by inhibiting its renal active tubular secretion without affecting the glomerular filtration rate.

The basolateral uptake transporter OAT2 and organic cation transporters OCT2 and OCT3 are assumed to transport creatinine. At physiologic creatinine concentrations, the specific activity of OAT2 transport is higher by a factor 2 than OCT2 or OCT3, so that OAT2 is a likely relevant creatinine transporter and further challenging the traditional view that a cationic pathway solely transports creatinine.

OAT2 facilitates the most efficient transport of creatinine in vitro of any of the human creatinine transporters, coupled with high expression levels in proximal tubules, suggests that it may make a substantial contribution to creatinine secretion in man and further establishes the more general involvement of anionic transporters in creatinine secretion. OAT2 facilitates creatinine transport with relatively high efficiency confirming the evidence the involvement of anionic transporters in creatinine secretion.

OAT3
Organic anion transporter (OAT) belong to the solute carrier family (SLC) 22 and play an essential role in the uptake of drugs, toxins, and nutrients.
OAT3 is primarily expressed in the kidney and plays a critical role in renal drug transport. The protein is an encoded integral membrane protein and appears to be localized to the basolateral membrane of renal proximal tubule cells.

OAT3 is a close homolog to OAT1. OAt3 is plentifully expressed on the basolateral membrane of proximal tubule cells as well as several on other epithelial tissues. Together with OAT1, it represents two of the most critical transporters involved in the renal uptake and excretion of a wide variety of drugs, exogenous toxins, nutrients, and endogenous metabolites, including uremic toxins.

Please visit the OAT1 color button to read more.

OAT1 and OAT3 have been shown to interact with many of these uremic toxins and solutes in vitro and considerable in vivo. Data indicate that the OATs also handle many endogenous metabolites, including some uremic toxins or retention solutes.

OAT3s are indirectly dependent on the inward sodium gradient. This drives the reentry of dicarboxylates into the cytosol. Dicarboxylates, for example, alpha-ketoglutarate generated within the cell, or recycled from the extracellular space, are used as exchange substrates to fuel the influx of organic anions against their concentration gradient.

OAT1 and 3 represent the first step in the active renal tubular secretion of negatively charged drugs and metabolites. They are involved in renal drug-drug interaction and toxicology.

Therefore, the FDA and EMA regulatory guidance recommend evaluation of OAT transporter interactions for NCEs and circulating metabolites, notably where significant renal elimination of negatively charged drugs is observed.

Literature
Regulation of Expression of Renal Organic Anion Transporters OAT1 and OAT3 in a Model of Ischemia/Reperfusion Injury

Screening of Drug-Transporter Interactions in a 3D Microfluidic Renal ProximalTubule on a Chip

Targeting Organic Anion Transporter 3 with Probenecid as a Novel Anti-Influenza A Virus Strategy

Anion transport and supramolecular medicinal chemistry

Requirements for human iPS cell-derived hepatocytes as an alternative to primary human hepatocytes for assessing absorption, distribution, metabolism, excretion and toxicity of pharmaceuticals

An Organic Anion Transporter 1 (OAT1)-centered Metabolic Network

A Human Renal Proximal Tubule Cell Line with Stable Organic Anion Transporter 1 and 3 Expression Predictive for Antiviral-Induced Toxicity

OAT Inhibitors and Assays
Pharmacokinetics and other clinical effects of drugs are dramatically influenced by transporter-mediated drug-drug interactions in the kidney. The significant transporters in the basolateral membrane of the kidney proximal tubes are the human organic anion transporters hOATP1 and hOATP3. They mediate the rate-limiting step in the elimination of a broad spectrum of drugs.

OAT Clinical Importance

OATs are critical to the entry of drugs into the renal proximal tubules for renal excretion. A combination of an OAT substrate with an OAT inhibitor as part of a development strategy might fail. It might cause reduced renal clearance, higher plasma levels, or more negative side effects.

OAT Regulatory Significance

The EMA European Medicines Agency has published a
Guideline on the investigation of drug interactions, dated June 21, 2012.
Click here for Details.

The equivalent guidance from the US Food and Drug Administration (FDA) is dated October 2017 “Clinical Drug Interaction Studies — Study Design, Data Analysis, and Clinical Implications
Guidance for Industry DRAFT GUIDANCE”.
Click here for Details
The guidelines mention OAT1 and OAT3 as clinically relevant transporters. It is recommended to investigate the potential of inhibitors for OAT1 and OAT3 for all new drugs.

OAT Assays

The cellular uptake mechanism of transporters is crucial in the pharmacokinetic profile of many structurally unrelated drugs. Present at all important pharmacological barrier tissues, these proteins enable the translocation of medium to low permeability drug substances across plasma membranes, and thereby determine absorption, distribution, and elimination routing.

Testing for interactions with uptake transporters has the potential to predict the main factors in the system level movement of drugs. Assessing the inhibitory potential of test articles on uptake transporters may indicate drug-drug interaction implications.

Primacyt offers uptake transporter studies for the assessment of inhibition and substrate.

The purpose of OAT substrate assays is testing a given test article with a potential perpetrator compound for drug-drug interactions. The drug-drug interaction is measured as a change in the pharmacokinetics comparing the concentration of the first drug, the victim, against the changes caused by the perpetrator drug. An OAT inhibition assay uses a directly predefined uptake transporter.


Asssessment Studies

Inhibitor Asssessment Studies


The assay measures the inhibitory potential of the test article (TA) on the uptake transporter-mediated transport of a labeled probe substrate. The assay is performed with cold test article. Using the selected human uptake transporter, the probe substrate is transported into the transfected cells.

Values are presented on a relative scale with a definition of 100% as transport in the presence of the solvent together without test article at no inhibition. Zero percent means no and test article at no inhibition. Zero percent is set as transport without activity of the transporter.

IC50 is defined as concentration required to inhibit the transport of the reporter substrate by 50%. Such assay provides information on any interaction (either substrate or inhibitor) between selected uptake transporters and the investigated test article that would affect the transport of the probe substrate.

Due to non-availability of new compounds or for repositioning purposes, combination therapies gain importance for drugs of different therapeutic classes. This might increase the risk for significant drug-drug interactions amongst these drugs.

Risk containment is essential to control adverse drug-drug interaction relevant to the respective patient population by using appropriate in vitro tools to secure customized clinical interaction studies in drug development.


Substrate assessment studies

The assessment of substrate typically occurs after an inhibition study but can be performed in separate phases in the framework of our services.

Primacyt Standard workflow for the characterization of DDIs

Phase 1: Confirmation if uptake of a cold or isotope-labeled compound can be measured, whereas the transporter mediates the uptake.
The expected outcome is the determination of whether or not the uptake transporter-mediated uptake of the cold (or isotope-labeled) compound into the cells can be measured directly by analytical methods.

Phase 2: Kinetic Transport Characterization
The Inhibition of transport is typically analysed using a known substrate and inhibitor, utilized as a probe substrate and reference inhibitor in the prior inhibition study. For known inhibitors/substrates the effect on the transport of the test article will be investigated at the optimized concentration of the test article and multiple predefined concentrations of the inhibitor/substrate molecule. The outcomes are KM and Vmax values.

Phase 3: Assessment of meaningful drug-drug interactions.

Measurement of the IC50 as described above for certain perpetrator drugs on the transport of the test article.


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You have reached this page because you might be interested in the following topic areas:
Human OATs, OAT family, Renal excretion, anion transporter. Also antiviral drugs, organic transit, protein kinase, sodium independent issues, proximal tubule cells or organic anion, ,plasma levels, substrate specificity, renal proximal tubules, organic anion transporters oats as well as basolateral membrane, uric acid, renal elimination ans organic anion transporting polypeptide.