In vitro selection of the most relevant species to predict human renal toxicity
Tissue
Models of the NephronThe problem and data requirement
The client had observed different pharmacodynamics in vivo between rat and dogs when dosed with an active ingredient. They needed to understand the mechanism underlying these differences and determine which animal model was the most relevant to human to support a regulatory submission.
Solution
Step 1:
Our experts worked with the customer to understand the problem
With a confidentiality agreement in place, the customer outlined that in vivo studies using the cereal herbicide MCPA (4-chloro-2-methylphenoxyacetic acid) identified the kidneys as the primary target organ following oral dosing in rat and dog; the data showed marked differences in the kidney clearance in dogs. The customer needed to understand whether the dog or rat data was predictive of drug behaviour in humans.
Step 2:
We designed a study protocol that efficiently provided data of value
The preliminary data from the customers studies indicated the transporter OAT1 was involved the kidney. We recommended suitable concentrations and time points in a study using our 24-well human, rat and dog proximal tubule cell assays under known inhibitors of OAT1 that included Probenecid. A full statement of work (SOW) was prepared and agreed with the client.
Step 3:
From initiation to data in three months
The full study assessed the absorption and excretion of the test article MCPA and another compound in three biological and technical repeats, four concentrations and in three species human, rat and dog assays. The study was completed in three months post contract agreement.
Step 4:
Expert data interpretation to support regulatory submission
After the 70-point data set was quality assessed and then sent to the customer, we consulted with them on the interpretation. A full report was drafted and agreed with the customer to support the registration of the active ingredient. The results were published: Gledhill et al., (2022).Xenobiotica. The chlorophenoxy herbicide MCPA: A mechanistic basis for the observed differences in toxicological profile in humans and rats versus dogs.
Outcomes for the client
Our analysis confirmed that MCPA is transported by OAT1 but not exclusively. It also showed that rat is more relevant to human than dog as a model to evaluate the nephrotoxicity risk of this particular herbicide.
