Müller S, Dunker R, Hochhaus G
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, USA.
Pharmazie. 1996 Aug;51(8):581-5.
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.
肽的酶促裂解可能会释放出具有不同药理特性的代谢产物。当利用动物数据预测人类情况时，肽代谢的种间差异可能是一个潜在的误差来源。因此，研究了强啡肽（Dyn）A1-13在实验中常用的各种物种（猴、兔、大鼠、豚鼠）血浆中的代谢情况，并与先前报道的人类数据进行了比较。通过酶抑制和动力学分析评估代谢途径，两者得出的结果几乎相同。在所有物种中，所有强啡肽片段均观察到快速代谢（半衰期从豚鼠血浆中Dyn A1-12的0.3分钟到猴血浆中Dyn A2-12的2.6分钟）。Dyn A1-13的代谢主要在半衰期方面有所不同（从豚鼠血浆中的0.5分钟到猴血浆中的1.1分钟），而不同物种的代谢途径相似（Dyn A1-13的主要代谢产物Dyn A1-12：从豚鼠血浆中的88%到兔血浆中的71%）。Dyn A1-13最重要的代谢产物Dyn A1-12的代谢命运在不同物种间比Dyn A1-13的代谢命运更加多样化。对于初步评估而言，除豚鼠外，所有研究物种血浆中Dyn A1-13的代谢途径和速率与人类血浆中的代谢途径和速率足够相似。
