Species differences in the intra-brain distribution of an L-type amino acid transporter 1 (LAT1) -utilizing compound between mice and rats

The prodrug approach targeting influx transporters has been extensively studied as a means of central nervous system drug delivery. Transporter and enzyme expression, localization and activity may contribute to significant species differences in preclinical studies. However, data about the possible species differences in the intra-brain distribution of transporter utilizing compounds is scarce. Here, we investigated the species differences in the intra-brain distribution of an L-type amino acid transporter 1 (LAT1)-utilizing L-lysine analogue of ketoprofen (KPF) (compound 1) and KPF itself by the whole tissue and brain microdialysis methods in mice, and compared the results to those previously reported in rats. Their pharmacodynamic responses in both species were assessed by measuring the brain prostaglandin E-2 (PGE(2)) levels by LC-MS/MS. The intracellular delivery of compound 1 was much lower in mice than in rats. Higher target site concentrations of compound 1 and released KPF were reflected on a more pronounced effect on PGE(2) levels in the rat brain. In conclusion, these results highlight the need for cross-species characterization of prodrug pharmacokinetics and pharmacodynamics in preclinical studies.

Automated summary

The study found significant species differences in the intra-brain distribution of compounds utilizing L-type amino acid transporter 1 between mice and rats, with more pronounced effects in rats. These results underscore the importance of cross-species characterization of prodrug pharmacokinetics and pharmacodynamics in preclinical studies.