When rats and dogs were dosed with an active component, the client noticed their pharmacodynamics in vivo differed. The client wanted to understand the mechanism underlying these differences and decide which animal model was most relevant to humans for supporting a regulatory submission.
Image Credit: Newcells Biotech
Solution
Step 1:
Newcells’ experts worked alongside the client to determine the issue
Implementing a confidentiality agreement, the client explained 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 dogs and rats; the data revealed significant differences in kidney clearance in dogs.
The client wanted to know if the data from dogs or rats predicted drug behavior in people.
Step 2:
Newcells developed a study protocol that efficiently offered data of value
The preliminary data from the client’s investigations revealed that the transporter OAT1 was involved in the kidney. Newcells advised appropriate concentrations and time points in a study using its 24-well dog, human, and rat proximal tubule cell tests with known OAT1 inhibitors, including Probenecid.
A complete statement of work was created and agreed upon with the client.
Step 3:
From initiation to data in three months
The study evaluated the absorption and excretion of the test article MCPA and another substance in three biological and technical replicates, four concentrations, and three species (dog, human, and rat). It was finished three months after the contract agreement.
Step 4:
Expert data interpretation to support regulatory submission
After quality-checking the 70-point data set and sending it to the client, Newcells consulted with the client on the interpretation. A comprehensive report was prepared and agreed upon with the customer to support the registration of the active component.
The results have been published in Xenobiotica, explaining the differences in the toxicological effects of the chlorophenoxy herbicide MCPA in humans, rats, and dogs ("The chlorophenoxy herbicide MCPA: A mechanistic basis for the observed differences in toxicological profile in humans and rats versus dogs." Gledhill et al., 2022).
Client outcomes
This research indicated that OAT1 transports MCPA, although not exclusively. It also demonstrated that rats are more relevant to humans than dogs as models for assessing the nephrotoxicity risk of this specific herbicide.
About Newcells Biotech
Newcells Biotech develops in vitro cell-based assays for drug and chemical discovery and development.
Using our expertise in induced pluripotent stem cells (iPSCs), cellular physiology, and organoid technology, we build models that incorporate the “best biology” for predicting in vivo behavior of new drugs.
Our experts have developed and launched assays to measure transporter function, safety, and efficacy in a range of cell and tissue types, including kidney, retina and lungs.
We have the capability to develop and implement protocols to measure cilia beat frequency and toxicity on small airway epithelial cells model, retinal toxicity and disease modelling on retinal organoids and retina epithelium, as well as drug transport in the kidney, DDI and nephrotoxicity across human and a range of preclinical species.
Sponsored Content Policy: News-Medical.net publishes articles and related content that may be derived from sources where we have existing commercial relationships, provided such content adds value to the core editorial ethos of News-Medical.Net which is to educate and inform site visitors interested in medical research, science, medical devices and treatments.