Swart P J, Oelen W E, Bruins A P, Tepper P G, de Zeeuw R A
Department of Analytical Chemistry and Toxicology, University Centre for Pharmacy, Groningen, The Netherlands.
J Anal Toxicol. 1994 Mar-Apr;18(2):71-7. doi: 10.1093/jat/18.2.71.
The metabolism of the dopamine D2 agonist N-0923 was investigated by an in vitro isolated liver perfusion. Determining the metabolic profile and identity of the different metabolites was achieved by using high-performance liquid chromatography with UV detection, combined with atmospheric pressure ionization mass spectrometry. Using this technique, no extensive sample cleanup is required, and the studies can be performed without radioactivity. In addition to previously observed metabolites, nine new metabolic products were identified. All metabolites were exclusively excreted into the bile, except for the despropyl metabolite, which was also detectable in the perfusate. 5-O-Glucuronidation and N-depropylation followed by 5-O-glucuronidation are the most important metabolic routes. N-dealkylation of the thienylethyl group followed by 5-O-glucuronidation and sulfation is a second major metabolic pathway. Catechol formation of the despropyl metabolite with or without subsequent conjugation was not found. Catechol formation of the desthienylethyl metabolite occurred, but only its glucuronide conjugates were found. This study complements previous results of in vivo metabolic studies using the radiolabeled racemate N-0437, and it explains differences in bile excretion during isolated liver perfusions using N-0923 and radiolabeled N-0923.
通过体外离体肝脏灌注研究了多巴胺D2激动剂N-0923的代谢情况。采用高效液相色谱-紫外检测联用大气压电离质谱法确定了不同代谢物的代谢谱及其结构。使用该技术无需进行大量的样品净化处理，并且研究可以在无放射性的情况下进行。除了先前观察到的代谢物外，还鉴定出了九种新的代谢产物。所有代谢物都专门排泄到胆汁中，但去丙基代谢物除外，其在灌注液中也可检测到。5-O-葡萄糖醛酸化和N-去丙基化后再进行5-O-葡萄糖醛酸化是最重要的代谢途径。噻吩乙基的N-脱烷基化后再进行5-O-葡萄糖醛酸化和硫酸化是第二条主要代谢途径。未发现去丙基代谢物形成儿茶酚，无论其随后是否发生结合。去噻吩乙基代谢物形成了儿茶酚，但仅发现了其葡萄糖醛酸共轭物。本研究补充了先前使用放射性标记的外消旋体N-0437进行的体内代谢研究结果，并解释了使用N-0923和放射性标记的N-0923进行离体肝脏灌注期间胆汁排泄的差异。
