Accurate prediction of human drug toxicity is a major challenge in drug development. It is estimated that around 50% of the pre-clinical, in vivo screening of new potential drug molecules in rat fail to predict subsequent human toxicity. Regulatory authorities recognise the poor performance of current in vivo screening and have called for the development of alternative in vitro cell based screening assays to reduce and replace current animal testing in pre-clinical screening.
In this project, we aim to characterise and validate primary renal proximal tubule models from human and rat kidney as in vitro platform for drug safety studies. We will measure species differences in the handling of key molecules between rat kidney proximal tubule cells and human kidney proximal tubule cells to predict human toxicity. To do this we will generate in vitro – in vivo correlations for the handling of a wide range of drug molecules of diverse chemistries and renal clearance rates in both models. With these models in place we will gain clear unambiguous transport data and be able to compare, at an early stage, the handling of molecules in very similar in vitro models derived from rat kidney and human kidney. With these two screening platforms in place, not only would there be an in vitro platform to investigate drug handling in either species, but crucially, direct comparison of the renal handling of a molecule between rat and human kidney would flag up differences in handling that might impact on the progress of a candidate drug molecule into a pre-clinical animal study.
Acceptance of our models would result in the replacement of significant numbers of animals in drug testing with a more predictive in vitro assay.
Kumar V et al. (2018). The Importance of Incorporating OCT2 Plasma Membrane Expression and Membrane Potential in IVIVE of Metformin Renal Secretory Clearance. Drug Metabolism and Disposition 46(10):1441-1445. doi: 10.1124/dmd.118.082313
Prasad B et al. (2016). Abundance of Drug Transporters in the Human Kidney Cortex as Quantified by Quantitative Targeted Proteomics. Drug Metabolism and Disposition 44(12):1920-24. doi: 10.1124/dmd.116.072066
Jenkinson SE et al. (2012). The limitations of renal epithelial cell line HK-2 as a model of drug transporter expression and function in the proximal tubule. Pflügers Archiv European Journal of Physiology 464(6):601-11. doi: 10.1007/s00424-012-1163-2
- 2017 PhD Studentship Review: Case Study