Cross Species Comparison of Drug Handling - Newcells

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An in vitro, light responsive, retinal model for accurate predictions of in vivo outcomes you can have confidence in.

aProximateTM

Kidney platform

The most advanced near-physiological high throughput kidney proximal tubule cells (PTC) model to investigate drug transport modalities in vitro.

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Lung model

A model to investigate airway physiology, viral infection, drug safety and environmental impacts on lung airway epithelia.

Sinusoid iPSC-derived Liver model

Liver model

We are developing a model of liver sinusoid derived from human induced pluripotent stem cells (iPSC).

Cross Species Comparison of Drug Handling

aProximate™ platform: The most advanced near-physiological high throughput kidney proximal tubule cells (PTC) model is available from a range of species to allow cross species comparison and in vitro-in vivo extrapolation (IVIVE) to improve clinical outcomes predictions in humans.

Validated model: The aProximate™ platform is validated for a range of species allowing direct cross species comparison of drug transport pathways. The use of such a reliable in vitro tool helps de-risk drug discovery.

Drug handling in different species

Cross-species drug handling and transport assays are performed on mouse knock-out (KO) model or other preclinical species. However due to species differences, those models are not always as predictive of human responses as expected. A more detailed understanding of how new drugs are transported and eliminated through the kidney at the transporter level in the chosen preclinical models is paramount to mitigating the risk of renal toxicity in humans. To this end robust comparative in vitro models, such as the aProximate™ platform, are needed to improve vitro-in vivo extrapolation (IVIVE).

Case study: Cross species comparison of PAH excretion

Para-aminohippurate (PAH), a derivative of hippuric acid, is used as a diagnostic agent for the measurement of renal plasma flow. When infused intravenously (IV), PAH is largely extracted from the blood by OAT1, the classic PAH transporter. Addition of probenecid, an OAT1 inhibitor, reduces PAH clearance due to drug-drug interactions at the transporter level.

Handling of PAH

Handling of PAH is known to be different in different preclinical species with a net excretion of PAH in humans and rats compared to a net absorption in dogs. PAH excretion was evaluated in vitro using aProximate™ PCTs from 4 different species to determine if the differences in PAH handling could be detected in vitro.

Cross species differences (Human, dog, rat)

The cross species difference in PAH drug handling observed in vivo was confirmed in vitro by comparing PAH flux data in human, rat and dog aProximate™ PTCs in the absence and presence of probenecid, which reduces OAT1 transport. Measure of PAH apical to basolateral flux (JAB), basolateral to apical flux (JBA) and net flux (JNet) showed a net secretion of PAH in human, non-human primates, and rat aProximate™ PTCs and a net absorption in dogs. In summary, aProximate™ is an ideal model to test drug handling and drug safety in different species in vitro prior to selecting preclinical species. The ability to reliably predict drug transport mechanisms contributes to the Nc3R (National Centre for replacement, refinement, and reduction of animals in research) goals, aiming to reduce animal studies for investigational studies of the kidney.

Cross species comparison of drug handling
Cross-species comparison of PAH drug handling in human, dog and rat aProximate™ proximal tubule cells. Apical to basolateral flux (JAB), basolateral to apical flux (JBA) and net flux (JNet) suggest a net secretion of PAH in human and rat aProximate™ proximal tubule cells but a net absorption in dog aProximate.

Newcells aProximate™ platformDe-risk your drug discovery pipeline

Accelerate your research with a reliable and consistent supply of proximal tubule cells validated for drug safety & efficacy as well and drug transporter assays. The highly predictive platform provides detailed mechanistic insights into drug handling.  
Using in vitro aProximate™ platform accelerates and de-risk drug discovery and reduces the requirement for animal experiments for investigational studies of the kidney. 

aProximate™ The most advanced near-physiological high throughput kidney proximal tubule cell (PTC) model.

Recapitulates Proximal tubule physiology

  • Expression of all key renal transporters 
  • High throughput solution for industry 
  • Outperforms competitor in vitro models 
  • FDA approved kidney biomarkers 
  • Enables mitochondrial health monitoring 
Proximal tubule physiology

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RESOURCES:  

In vitro models for accurate prediction of renal tubular xenobiotic transport in vivo . Vriend J. et al., Current Opinion in Toxicology, 2021, Vol 25,2021, Pages 15-22,ISSN 2468-2020, https://doi.org/10.1016/j.cotox.2020.12.001.

Freshly isolated primary human proximal tubule cells as an in vitro model for the detection of renal tubular toxicity. Bajaj et al., Toxicology. 2020 Sep;442:152535. doi: 10.1016/j.tox.2020.152535. Epub 2020 Jul 2.  

In vitro platforms for de risking nephrotoxicity during drug development, Brown and Primrose, Drug Target Review, Sept 2020. 

Derivation of a System-Independent Ki for P-glycoprotein Mediated Digoxin Transport from System-Dependent IC50 Data. Chaudhry A, et al., Drug Metab Dispos. 2018 Mar;46(3):279-290. doi: 10.1124/dmd.117.075606. Epub 2018 Jan 9.  

Characterisation of human tubular cell monolayers as a model of proximal tubular xenobiotic handling Brown CD et al., Toxicol Appl Pharmacol. 2008 Dec 15;233(3):428-38. doi: 10.1016/j.taap.2008.09.018. Epub 2008 Oct 1. PMID: 18930752. 

Abundance of Drug Transporters in the Human Kidney Cortex as Quantified by Quantitative Targeted Proteomics. Prasad B,. etal., Drug Metab Dispos. 2016 Dec;44(12):1920-1924. doi: 10.1124/dmd.116.072066. Epub 2016 Sep 12.  

Predictive in vitro primary proximal tubule models for understanding nephrotoxicity in drug develppment programs. Brown C., March 2020, Webinar  

Reducing compound attrition by predicting renal tubular toxicity with in vitro PTEC models. Brown C., Sept 2020, Webinar