Müller S, Hochhaus G
Department of Pharmaceutics, University of Florida, Gainesville 32610, USA.
Pharm Res. 1995 Aug;12(8):1165-70. doi: 10.1023/a:1016211910107.
A detailed investigation of the metabolic routes and rates of Dyn A1-13 in human blood and plasma was performed.
Human plasma was incubated at 37 degrees C with dynorphin A 1-13 (Dyn A1-13, 15-20 microM). The generated dynorphin fragments were separated by a new ion-pair chromatographic method and identified by matrix assisted laser desorption mass spectroscopy. The kinetic behavior of parent compound and metabolites was evaluated in the absence and presence of enzyme inhibitors.
The major plasma metabolites of Dyn A1-13 were Dyn A1-12, A2-12, A4-12 and A4-8. Further metabolites were Dyn A2-13, A3-13, A3-12, A5-12, A6-12, A7-12, A1-10, A2-10, A2-8 and A3-8. At 37 degrees C, Dyn A1-13 had a half-life of less than one minute in plasma and blood. Plasma half-lives of major metabolites ranged between 0.5 and 4 min. Inter- and intra-individual differences in healthy volunteers were 30% (c.v.). Dyn A1-13 is mainly metabolized by carboxypeptidases to Dyn A1-12 (80%) and by aminopeptidases to Dyn A2-13 (15%). Dyn A1-12 and Dyn A2-13 are predominantly converted into Dyn A2-12 (67% of Dyn A1-13). Subsequent metabolic steps yield Dyn A3-12 (16%), Dyn A4-12 (37%) and Dyn A4-8 (33%). Aminopeptidases generate Dyn A2-12, A3-12, A4-12, A5-12. ACE metabolizes Dyn A1-12 (19%), A2-12 (33%), A3-12 (34%) and A4-12 (46%). Bestatin-sensitive endopeptidases (possibly endopeptidase 24.11) metabolize 30% of Dyn A2-12. Dyn A4-8 is formed via Dyn A4-12 (23% of Dyn A4-12) and Dyn A2-10 (37% of Dyn A2-10).
The combination of enzyme inhibition experiments and noncompartmental kinetic analysis proved to be a powerful tool for the detailed evaluation of the metabolic fate of Dyn A1-13 in human blood and plasma.
对强啡肽A1-13（Dyn A1-13）在人体血液和血浆中的代谢途径及速率进行详细研究。
将人血浆与强啡肽A 1-13（Dyn A1-13，15 - 20微摩尔）在37℃下孵育。通过一种新的离子对色谱法分离生成的强啡肽片段，并通过基质辅助激光解吸质谱法进行鉴定。在不存在和存在酶抑制剂的情况下评估母体化合物和代谢物的动力学行为。
Dyn A1-13的主要血浆代谢物为Dyn A1-12、A2-12、A4-12和A4-8。其他代谢物为Dyn A2-13、A3-13、A3-12、A5-12、A6-12、A7-12、A1-10、A2-10、A2-8和A3-8。在37℃时，Dyn A1-13在血浆和血液中的半衰期小于1分钟。主要代谢物的血浆半衰期在0.5至4分钟之间。健康志愿者个体间和个体内差异为30%（变异系数）。Dyn A1-13主要通过羧肽酶代谢为Dyn A1-12（80%），通过氨肽酶代谢为Dyn A2-13（15%）。Dyn A1-12和Dyn A2-13主要转化为Dyn A2-12（占Dyn A1-13的67%）。随后的代谢步骤产生Dyn A3-12（16%）、Dyn A4-12（37%）和Dyn A4-8（33%）。氨肽酶产生Dyn A2-12、A3-12、A4-12、A5-12。血管紧张素转换酶（ACE）代谢Dyn A1-12（19%）、A2-12（33%）、A3-12（34%）和A4-12（46%）。贝抑素敏感的内肽酶（可能是内肽酶24.11）代谢30%的Dyn A2-12。Dyn A4-8通过Dyn A4-12（占Dyn A4-12的23%）和Dyn A2-10（占Dyn A2-10的37%）形成。
酶抑制实验和非房室动力学分析相结合被证明是详细评估Dyn A1-13在人体血液和血浆中代谢命运的有力工具。
