Are mice, rats, and rabbits good models for physiological, pharmacological and toxicological studies in humans?

In the mammalian kidneys, handling of various organic compounds is mediated by multispecific organic anion and cation transporters localized in the luminal and contraluminal cell membrane domains of specific nephron segments, largely in proximal tubules. These transporters are responsible for cellular uptake and/or elimination of endogenous and xenobiotic organic compounds, including various anionic and cationic drugs, thus contributing to their reabsorption and/or secretion along the nephron. Recent studies have indicated a pivotal role of these transporters in drug resistance, drug-drug interactions, and drug-induced nephrotoxicity, whereas the presence of disfunctional transporters due to truncated isoforms or point mutations can cause genetic diseases. In rat, mouse and rabbit nephrons, a number of these transporters exhibit sex differences in their protein and/or mRNA expression. In comparison with the expression in rodents and rabbits, in the human nephrons some transporters are absent, some exhibit different localization in the cell membrane domains, and none exhibit the sex-dependent expression. Species differences in some transporters have been further demonstrated concerning substrate selectivity, distribution in cells along the nephron, levels of mRNA and/or protein expression, sensitivity to inhibitors, and regulation. Overall these differences in the mammalian kidneys indicate that: a) data on the membrane transporters-related functions in one species can not simply be regarded as relevant for other species, and b) many physiological, pharmacological, and toxicological findings related to organic anion and cation transport and transporters in rodents and rabbits do not reflect the situation in humans.