Cross Species Comparison

Para-aminohippurate (PAH), a derivative of hippuric acid, is used as a diagnostic agent for the measurement of renal plasma flow. When infused intravenously, PAH is largely extracted from the blood by OAT1, the classic PAH transporter. The addition of probenecid, an OAT1 inhibitor, reduces PAH clearance due to drug-drug interactions at the transporter level. Handling of PAH is known to vary in different preclinical species with a net excretion of PAH in human and rats  compared to a net absorption in dogs.

PAH excretion was evaluated in vitro using aProximate™ PTCs from four different species to determine if the differences in PAH handling could be detected in vitro. 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 PTCs in the absence and presence of probenecid, which reduces OAT1 transport. Measurement of PAH apical to basolateral flux (J_ab), basolateral to apical flux (J_ba) and net flux (J_net) showed a net secretion of PAH in human, non-human primates, and rat PTCs and a net absorption in dogs. In summary, aProximate™ is an ideal kidney transporter model to test drug handling and drug safety in different species in vitro prior to selecting preclinical species.

Newcells has investigated renal toxicology following exposure to the herbicide MCPA (4-chloro-2-methylphenoxyacetic acid) to elucidate the molecular basis of species differences observed as part of a collaborative project (Gledhill et al., 2022).

MCPA is a globally registered herbicide to control broadleaf weeds in cereals. Toxicological investigations using MCPA identified the kidneys as the primary target organ following oral dosing in rat, mouse and dog. Toxicokinetics of MCPA and other derivatives in rodent and non-rodent models concluded that kinetic differences in the dog suggest that this species is less relevant to human risk assessment than rodents.

This work aimed to establish the molecular basis for the greater sensitivity of the dog to the toxic effects of MCPA compared with the human and rat. Part of the work consisted of in vitro renal transporter studies using Newcells‘ aProximate™ kidney transporter model comparing proximal tubule cell flux in rat, dog and human.

The data were evaluated as a whole to provide a mechanistic rationale for the higher systemic exposures in the dog compared to those seen in other species and support the lack of relevance of the dog as a model species for MCPA human health risk assessments.

Our service provides insights into cross-species differences in drug handling: aProximate™ is available in multiple species such as human, rat, dog and NHP, making it the ideal kidney transporter model for assessment of cross-species comparison of drug handling.

Perform rapid in vitro species comparison to select the best preclinical species and progress lead compounds into clinical development by using our transporter assays.

The cross-species comparative data generated from our transporter assays have been used for IND and IMPD submissions as it provides detailed mechanistic insights into drug excretion in several species, explaining possible differences.

Our project timelines are short due to our regular supply of fresh kidney tissue. The robust data generated by our scientific experts will guide you in confidence for key decision-making steps during drug development.

An example of cross-species drug interaction packages includes assessment of transepithelial flux in proximal tubule cells, specifically Apical to Basal (J_ab) and Basal to Apical (J_ba) flux, as well as net transport measurements in rat, dog and human. We can also measure the magnitude of intracellular accumulation across both the apical and basolateral membranes. We recommend acquiring data from three separate biological donor kidneys across all species.