Functional and Pharmacological Comparison of Human, Mouse, and Rat Organic Cation Transporter 1 toward Drug and Pesticide Interaction

Abstract

Extrapolation from animal to human data is not always possible, because several essential factors, such as expression level, localization, as well as the substrate selectivity and affinity of relevant transport proteins, can differ between species. In this study, we examined the interactions of drugs and pesticides with the clinically relevant organic cation transporter hOCT1 (SLC22A1) in comparison to the orthologous transporters from mouse and rat. We determined Km-values (73 ± 7, 36 ± 13, and 57 ± 5 µM) of human, mouse and rat OCT1 for the commonly used substrate 1-methyl-4-phenylpyridinium (MPP) and IC50-values of decynium22 (12.1 ± 0.8, 5.3 ± 0.4, and 10.5 ± 0.4 µM). For the first time, we demonstrated the interaction of the cationic fungicides imazalil, azoxystrobin, prochloraz, and propamocarb with human and rodent OCT1. Drugs such as ketoconazole, clonidine, and verapamil showed substantial inhibitory potential to human, mouse, and rat OCT1 activity. A correlation analysis of hOCT1 versus mouse and rat orthologs revealed a strong functional correlation between the three species. In conclusion, this approach shows that transporter interaction data are in many cases transferable between rodents and humans, but potential species differences for other drugs and pesticides could not be excluded, though it is recommendable to perform functional comparisons of human and rodent transporters for new molecular entities.

Influence of YES1 Kinase and Tyrosine Phosphorylation on the Activity of OCT1

“…The notion that the OCT1-inhibitory properties of dasatinib are species-independent is consistent with and recapitulates several prior observations ( Shu et al, 2007 ; Sprowl et al, 2016 ; Floerl et al, 2020 ; Meyer et al, 2020 ), and suggests that mice can serve as a suitably predictive model for humans. To directly assess the influence of dasatinib on the function of OCT1 in vivo , the pharmacokinetic profile of TEA was examined in wild-type mice and OCT1/2-deficient mice receiving a single oral dose of dasatinib, given 30 min before the administration of TEA.…”

General Overview of Organic Cation Transporters in Brain

“…Regional differences in expression compared to OCT1, OCT2, and PMAT and differences in regulation including the high sensitivity of OCT3 to corticosterone (Table 4) effectuate the diversification of neurotransmitter reuptake in brain. (Engel and Wang 2005;Engel et al 2004;Floerl et al 2020;Fraser-Spears et al 2019;Gorboulev et al 1997;Gründemann et al 1994;Haenisch and Bönisch 2010;Hayer-Zillgen et al 2002;Miura et al 2017;Shirasaka et al 2017;Zhang et al 1998), corticosterone: Arndt et al 2001;Engel and Wang 2005;Engel et al 2004;Fraser-Spears et al 2019;Gründemann et al 1998bGründemann et al , 2002Hayer-Zillgen et al 2002;Minematsu et al 2010;Miura et al 2017;Wu et al 1998a;…”

Organic Cation Transporters in the Lung—Current and Emerging (Patho)Physiological and Pharmacological Concepts

“…When using other species, the consideration of any potential species differences in OCT/Ns' activity between laboratory animals and human is of crucial importance. In this Special Issue, Floerl and colleagues demonstrate a good functional correlation between rat, mouse and human OCT1 in terms of interactions between a number of investigated drugs [143]. Other OCT/Ns expression and activity profiles, however, still need to be thoroughly investigated in these models.…”