Kiang C H, Lee C, Kushinsky S
Department of Analytical and Metabolic Chemistry, Syntex Research, Palo Alto, CA 94304.
Drug Metab Dispos. 1989 Jan-Feb;17(1):43-8.
A new metabolite of naproxen, 6-desmethylnaproxen sulfate (6-DMNS), has been identified in plasma from normal and uremic subjects after oral administration of a single 500 mg dose of naproxen. Tentative identification was achieved by the finding of an increase in the concentration of 6-DMN upon incubation of the plasma with arylsulfatase from Helix pomatia or from Aerobacter aerogenes. More definitive identification was established through demonstration that the HPLC retention time of the conjugate is identical to that of an authentic reference sample of 6-DMNS. Unequivocal identification was accomplished by means of LC-MS after the metabolite was isolated from the plasma by protein precipitation with acetonitrile and further purified by anion-exchange and reversed phase HPLC. Plasma profiles of 6-DMNS for normal and uremic subjects, obtained by a procedure involving differential enzymatic hydrolysis using arylsulfatase from H. pomatia, revealed that 6-DMNS was present in plasma from all subjects but in relatively high concentrations only in subjects with impaired renal function and that the extent of the conjugation is related directly to the severity of the dysfunction. No evidence was found for the presence of glucuronide or sulfate conjugates of naproxen in plasma.
在正常受试者和尿毒症受试者口服单次500毫克剂量萘普生后的血浆中，已鉴定出一种新的萘普生代谢产物，即6-去甲基萘普生硫酸盐（6-DMNS）。通过将血浆与来自苹果螺或产气气杆菌的芳基硫酸酯酶一起孵育后发现6-去甲基萘普生（6-DMN）浓度增加，初步鉴定得以实现。通过证明缀合物的高效液相色谱保留时间与6-DMNS真实参考样品的保留时间相同，建立了更明确的鉴定。在用乙腈进行蛋白质沉淀从血浆中分离出代谢产物并通过阴离子交换和反相高效液相色谱进一步纯化后，通过液相色谱-质谱法完成了明确鉴定。通过使用来自苹果螺的芳基硫酸酯酶进行差异酶促水解的程序获得的正常受试者和尿毒症受试者的6-DMNS血浆谱显示，所有受试者的血浆中均存在6-DMNS，但仅在肾功能受损的受试者中浓度相对较高，并且缀合程度与功能障碍的严重程度直接相关。未发现血浆中存在萘普生的葡萄糖醛酸或硫酸盐缀合物的证据。
