Kidney Functional & Efficacy Study

Functional and efficacy studies include the 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. The magnitude of intracellular accumulation across both the apical and basolateral membranes is also determined as well as paracellular flux. Data can be derived from three separate biological donor kidneys across multiple species.

Our project timelines are short due to our rolling production of aProximate™ batches. The robust data generated by our scientific experts will guide you in confidence for key decision-making steps during drug development towards clinical translation.

Creatinine is an endogenous metabolite usually transported by OCT2 and MATE, However, drugs such as the immunomodulator pyrimethamine is also a substrate for basolateral OCT2 and apical MATE transporters. OCT 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 vitro, reproducing in vivo inhibition of OCT and MATE transporters by cimetidine and pyrimethamine leading to a decrease of 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. The correlation between in vivo and in vitro data shows that aProximate™ proximal tubule model is predictive of renal uptake studies and the investigation of the mechanisms of drug interactions in the kidney.

This study analysed the renal flux and excretion of MCPA in different species to understand the mechanistic basis for a greater sensitivity to MCPA observed during toxicokinetic studies in dogs.

In vitro determination of the net transport of MCPA shows a net secretion in rat and human of a similar magnitude but significantly less in dog, in line with in vivo observations. The net secretion of MCPA was also measured in the presence of probenecid, a OAT1 inhibitor and was significantly reduced in dog, confirming OAT1 as a main transporter for MCPA in this specie. In rat and human however, the inhibitor was less effective, suggesting a possible different transport mechanism, in agreement with the differences in MCPA transport seen in vivo.