Mizuma T, Benet L Z, Lin E T
Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Hachioji, Japan.
J Chromatogr B Biomed Sci Appl. 1998 Oct 23;718(1):153-62. doi: 10.1016/s0378-4347(98)00357-0.
Stability of furosemide glucuronide, the major metabolite of furosemide, was studied in order to accurately assess the glucuronidation of furosemide. Furosemide glucuronide was purified by high-performance liquid chromatography, and the mass spectrum of furosemide glucuronide showed the molecular ion peaks [M-H]- at 505 and 507 (m/z). Furosemide glucuronide was photodegraded to the compound, which was shown more hydrophilic than furosemide glucuronide by high-performance liquid chromatography assay. The photodegradation product of furosemide glucuronide was hydrolyzed to one of the photodegradation products of furosemide by beta-glucuronidase, indicating that the photodegradation product of furosemide glucuronide possessed a glucuronic acid moiety. Furthermore, the mass spectrum of the photodegradation product of furosemide glucuronide exhibited molecular ion peaks [M-H]- at 487 and [M-2H+2Na]- at 509, indicating the chlorine displacement of furosemide glucuronide by a hydroxyl group. Furosemide glucuronide was unstable in an aqueous solution (pH=7.4), and presumed acyl migration isomers of furosemide glucuronide (furosemide glucuronide-isomers) were detected by high-performance liquid chromatography equipped with photodiode array UV detector. The UV spectra of seven furosemide glucuronide-isomers were closely similar to that of furosemide glucuronide but not furosemide. Exposing a mixture of furosemide glucuronide and furosemide glucuronide-isomers to light resulted in the production of new compounds. UV spectra of photodegradation products of furosemide glucuronide-isomers were closely similar to those of photodegradation product of furosemide glucuronide. These results suggested that furosemide glucuronide-isomers were also photodegraded, resulting in the displacement of chlorine by a hydroxyl group as in furosemide glucuronide.
为准确评估呋塞米的葡萄糖醛酸化作用，对其主要代谢产物呋塞米葡萄糖醛酸苷的稳定性进行了研究。通过高效液相色谱法对呋塞米葡萄糖醛酸苷进行纯化，呋塞米葡萄糖醛酸苷的质谱显示分子离子峰[M-H]- 位于505和507（m/z）处。呋塞米葡萄糖醛酸苷经光降解生成一种化合物，通过高效液相色谱分析表明该化合物比呋塞米葡萄糖醛酸苷更具亲水性。呋塞米葡萄糖醛酸苷的光降解产物经β-葡萄糖醛酸酶水解为呋塞米的一种光降解产物，表明呋塞米葡萄糖醛酸苷的光降解产物含有葡萄糖醛酸部分。此外，呋塞米葡萄糖醛酸苷光降解产物的质谱显示分子离子峰[M-H]- 位于487处，[M-2H+2Na]- 位于509处，表明呋塞米葡萄糖醛酸苷中的氯被羟基取代。呋塞米葡萄糖醛酸苷在水溶液（pH = 7.4）中不稳定，通过配备光电二极管阵列紫外检测器的高效液相色谱法检测到了推测的呋塞米葡萄糖醛酸苷酰基迁移异构体（呋塞米葡萄糖醛酸苷异构体）。七种呋塞米葡萄糖醛酸苷异构体的紫外光谱与呋塞米葡萄糖醛酸苷的紫外光谱非常相似，但与呋塞米的紫外光谱不同。将呋塞米葡萄糖醛酸苷和呋塞米葡萄糖醛酸苷异构体的混合物暴露于光下会产生新的化合物。呋塞米葡萄糖醛酸苷异构体的光降解产物的紫外光谱与呋塞米葡萄糖醛酸苷的光降解产物的紫外光谱非常相似。这些结果表明，呋塞米葡萄糖醛酸苷异构体也会发生光降解，导致氯被羟基取代，如同呋塞米葡萄糖醛酸苷一样。
