A validated assay for drug transport and DDI studies
Our kidney proximal tubule epithelia (PTEC) cell assay (aProximate™) uses ethically sourced, primary human or animal cells, cultured as a polarised monolayer in a 96-well Transwell™ format, to assess drug xenobiotic kidney transport.
Current regulatory guidance advises further in vitro renal transport studies if ADME data suggests that active secretion of the parent drug is greater than or equal to 25% of total clearance. Understanding the interaction of new drugs with renal transporters is an important requirement to understand the potential for drug-drug interactions (DDIs) which can impact on clinical trial design and labelling requirements. The elimination of drugs via the kidney involves a combination of passive glomerular filtration, active tubular secretion and passive or active reabsorption, the latter two processes are mediated by transporters located on the apical and basolateral surfaces of the proximal tubule epithelia cells.
The use of polarised monolayers of cells expressing transporters is one of the in vitro assays recommended in regulatory guidance. By using a range of well-known transporter inhibitors and dosing a drug on the apical and basolateral sides it is possible to generate data on which transporters are important, net flux and potential DDIs.
It is important to consider species differences when designing renal elimination experiments, as there are known examples of differences between humans and pre-clinical species.
Our unique aProximateTM system
- Expresses all major transporter classes at higher levels than other cell line systems
- Can measure apical and basolateral transport flux for a wide range of compound types including AON’s, siRNA and peptides
- Compare cross species behaviour with human, rat, mouse, canine and non-human primate (NHP) systems
- Is ideal for confirming transporter processes in the kidney and drug-drug interaction (DDI) studies
- Is suitable for radiochemical or bioanalytical measurements
The renal proximal tubule epithelia is a specialised polarised cell layer in the kidney that is a major site of drug secretion and adsorption mediated by membrane located transporters. The aProximate assay format effectively recreates the polarised PTEC structure on a semi-permeable membrane with the cells reforming tight junctions and the functional characteristics of the in vivo nephron.
We collaborate with our customers to design protocols investigating:
A system for generating key data on drug renal pharmacokinetics
- Drug-drug interaction
- Involvement of major transporters in drug pharmacology
- Species drug handling differences
- Large molecule transport by megalin and cubilin
The aProximate™ 24-well Transwell™ format is a medium throughput system that has been used in over 100 industrial studies, including the generation of data for regulatory submissions.
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V Kumar, J Yin, S Billington, B Prasad, CDA Brown, J Wang, JD Unadkat. The importance of incorporating OCT2 plasma membrane expression and membrane potential in IVIVE of metformin renal secretory clearance. Drug Metabolism and Disposition. 2018; 46 (10): 1441-1445
A Chaudhry, G Chung, A Lynn, A Yalvigi, C Brown, H Ellens, M O’Connor. Derivation of a System-Independent Ki for P-glycoprotein Mediated Digoxin Transport from System-Dependent IC50 Data. Drug Metabolism and Disposition. 2018; 46 (3): 279-290