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Drug Transporter Interactions & DDI study

Newcells aProximate™ PTC model

Accelerate your lead compound selection by understanding and confidently predicting their mode of action in kidney proximal tubule tissue

1.

Fully differentiated and polarised kidney proximal tubule cells

2.

Expression of all relevant renal transporters

3.

High predictivity of in vivo physiology and clinical outcomes

Investigate renal drug transport modalities and drug interactions in vitro

Drug-Transporter and Drug-Drug interaction study: this service uses the aProximate™ PTCs model which retains high expression of the relevant transporters involved in drug handling, making it ideal for drug transporter and drug interaction studies. Transporters play a major role in the uptake and efflux of drugs across cellular membranes. Given the presence of Megalin and Cubilin in the model, two key uptake transporters for large molecules,  the model is particularly insightful to predict the transport or retention of antibody drug conjugates (ADCs), antibiotics, anti-sense oligonucleotides (ASO) and radiolabelled conjugate in the proximal tubule.

Drug interactions with transporter proteins are common and can act either as substrates and/or inhibitors, a role which is best identified during the early-stages of drug development to define the absorption, distribution, metabolism and excretion (ADME) profile. Cross-species comparison between human, rat, mouse and dog can also be added as part of this service. Using our scientific expertise, Newcells provides advanced predictive transporter assays to answer your specific requirements and understand potential drug-drug interactions of both small and large molecules.

Service outputs

  • Flux Assay: Apical to Basal (Jab) and Basal to Apical (Jba) flux
  • Net transport measurements
  • Uptake assays : measurement of intracellular drug and metabolite concentrations
  • Identification of transporter-mediated drug interactions
  • High content imaging data
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A graph of a mate2k drug interactions

DDI

Multiple species

24-well

"I have had a very positive experience working directly with the Newcells team using their aProximate™ complex in vitro kidney model in support of several drug transport projects. This model is the only one that can present elusive organic anion transporter (OAT1, OAT2, OAT3) functionality above and beyond the commonly reported organic cation transporter (e.g., OCT2, MATE1/2K) activity of other models.  This has enabled careful characterization of the transporters (OCT2 versus OAT2) involved in the secretory renal clearance of creatinine, a widely used biomarker of renal function in clinical studies (J Pharmacol Exp Ther. 2024 Jan 2;388(1):201-208)." David Rodrigues, PhD, ADME expert

Services

  • Drug transporter assays
  • Drug interactions assays
  • Flux and net transporter measurements
  • Measurement of intracellular drug and metabolite concentrations

Models

  • aProximate™ kidney Proximal Tubule Cells
  • from human, mouse, rat and dog

Timeline

  • 2-3 months
Service Overview Close Open

This service provides insights into drug-drug and drug-transporter interactions:

aProximate™ PTCs have high expression of all key transporters involved in drug absorption, excretion and drug interactions including OAT1 and OCT2 (Brown et al., 2008). Species comparison can also be carried out as part of this study since aProximate™ PTCs are available from multiple species including human, rat, dog and mouse.

Substrate assessment and inhibition services using our transporter assay are carried out rapidly to generate data necessary to progress lead compounds into clinical development. The data generated from our transporter assays has been used for IND submissions to provide comprehensive drug metabolism, transporter and drug interaction data by testing parameters which follows regulatory guidelines.

Our project timelines are short due to our regular supply of fresh kidney tissue. The robust data generated by our scientific experts will guide confident key decision-making steps during drug development.

An example of transporter-drug interaction packages includes assessment of transepithelial flux in proximal tubule cells, specifically Apical to Basal (Jab) and Basal to Apical (Jba) flux, as well as net transport measurements. In addition, is also possible too measure the magnitude of intracellular accumulation across both the apical and basolateral membranes. Data can be derived from three separate biological donor kidneys across multiple species.

Assays
Functional and efficacy study readouts flux (Jab, Jba), net transport (Jnet, intracellular accumulation, paracellular flux. The studies can be performed with radiolabelled, fluoresence compounds or compounds labelled with LC/MS probes
Models aProximate™ primary isolated kidney proximal tubule cells
Assay format 24-well Transwell® plates
Species Human
Rat
Mouse
Dog
Time points and replicates 0, 30, 60, 90, 120 minutes each in triplicate, Three kidney donors (recommended)
SKU No. KST00000H
KST00000R
KST00000M
KST00000D
Example 1: In vitro investigation of drug-drug interactions Close Open

The aProximate™ model has been tested for its ability to recapitulate the renal clearance of the drug probenecid. In vivo renal clearance of probenecid is significantly reduced by the co-administration of other drugs such as para-aminohippurate (PAH), furosemide, cidofovir or fexofenadine, indicating drug-drug interactions via renal transporters, OAT-1 and OAT-3. The aProximate™ model reproduces the interaction between PAH and probenecid observed in vivo. The figure below shows a significant reduction of PAH basolateral to apical flux (JBA) and net flux (JNet) measured in the presence of probenecid in aProximate™ PTCs. This observation demonstrates that aProximate™ recapitulates proximal tubule function and accurately predicts renal drug-drug interactions.

A reliable model to assess drug/drug interactions (DDI). In vivo renal clearance of drugs is reduced by the OAT inhibitor probenecid (upper panel). A similar effect is observed in vitro using the aProximate™ model (bottom panel).
Example 2: Predicting renal transport and retention of large molecules Close Open

Many in vitro models lack the full repertoire of transporters present in vivo, leading to inaccurate assessments of molecular transport and poor predictivity of data. Primary aProximate™ PTCs are unique as they present the highest expression levels of Megalin and Cubilin in an in vitro model, enabling accurate quantification and subsequent translatability of results for the uptake of large molecules including peptides, antibodies,  ADC and radioconjugates. This is essential for evaluating renal drug toxicity, metabolism, and retention mechanisms of novel therapeutics.

Apical uptake of radioconjugated peptide Megalin/Cubilin in rat PTC monolayers.

 

Characterisation of apical uptake of radioconjugate peptide using a 3H radiolabelled peptide in rat aProximate™. Quantification of Radioconjugate uptake showing apical uptake.

Radioconjugate peptide (3H labelled) uptake is shown to be apical, to be inhibited by Megalin/Cubilin inhibitors (LPS, ROS and RAP).

Uptake inhibitor study with 3H radiolabelled peptide. Flux inhibition and apical uptake is reduced in the presence of known inhibitors of Megalin/Cubilin by LPS, ROS and RAP.

Models from for this service

aProximate™ Proximal Tubule Cells

aProximate™ is one of the most advanced, near physiological, in vitro MPS kidney Proximal Tubule Cell (PTCs) models. aProximate™ PTCs are derived from fresh human kidney tissue and are grown on Transwells® where they remain well differentiated as a polarised cell layer that forms tight junctions.

A microscope image of a nephron model
ZO-1 Staining of tight junctions between aProximate™ proximal tubule cells
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