Drug Transporter Interactions & DDI study

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 (J_BA) and net flux (J_Net) 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.

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.

Inhibition of FITC-albumin uptake in human PTCs

Apical uptake of radioconjuted peptide Megalin/Cubilin in rat PTC monolayers

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

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 (J_ab) and Basal to Apical (J_ba) 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.