Interspecies comparison of in vitro plasma degradation of dynorphin A 1-13

Enzymatic cleavage of peptides might release metabolites with distinct pharmacological profile. Interspecies differences in the metabolism of peptides might represent a potential source of error when animal data are intended to predict the human situation. Therefore, the metabolism of dynorphin (Dyn) A1-13 was investigated in the plasma of various species used in experimental practice (monkey, rabbit, rat, guinea pig) and compared to previously reported human data. The metabolic pathways were evaluated by enzyme inhibition and kinetic analysis, both yielding almost identical results. Rapid metabolism was observed with all dynorphin fragments across all species (half-lives from 0.3 min for Dyn A1-12 in guinea pig plasma to 2.6 min for Dyn A2-12 in monkey plasma). The metabolism of Dyn A1-13 differed mainly with respect to the half-life (from 0.5 min in guinea pig plasma) to 1.1 min in monkey plasma), while the metabolic routes were similar across the species (Dyn A1-12 major metabolite of Dyn A1-13: from 88% in guinea pig plasma to 71% in rabbit plasma). The metabolic fate of Dyn A1-12, the most important metabolite of Dyn A1-13 is much more heterogeneous across the species then the one observed for Dyn A1-13. For a first assessment, the metabolic routes and rates of Dyn A1-13 in plasma of all investigated species, except from guinea pigs, resemble those in human plasma sufficiently.