Drug Transporter Interactions & DDI

The aProximate™ model has been tested for its ability to mimic 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 probecenid 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.

Several drugs and metabolites are handled by the same transporters. For example, creatinine, an endogenous metabolite, and the immunomodulating drug pyrimethamine are both substrates for basolateral OCT2 and apical MATE transporters. OATs and MATE transport organic anions, organic compounds like creatinine, but also organic cationic drugs, such as metformin, a common drug used to treat type 2 diabetes.

The excretion of creatinine can be blocked by administering transporter inhibitors such as cimetidine and pyrimethamine. In addition, inhibition of OCT and MATE transporters by cimetidine and pyrimethamine in vivo also reduces metformin renal clearance. Cimetidine interferes with the uptake of metformin by proximal tubule cells and pyrimethamine with efflux of metformin.  In vivo, this leads to a significant increase in systemic exposure and a decrease in metformin renal clearance because metformin and pyrimethamine compete for efflux mediated by MATEs. This data shows that our proximal tubule model enables the investigation of the mechanisms of drug interactions in the kidney.

Our service provides insights into drug 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). We also offer species comparison as aProximate™ PTCs are available from multiple species such as human, rat, dog and NHP.

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 by providing 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 you in confidence for 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. We can also 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.