普萘洛尔对映体人体葡醛酸化立体选择性代谢研究

 目的 测定健康志愿者口服一定量消旋普萘洛尔后尿中两种不同构型普萘洛尔葡醛酸苷的排泄量，研究普萘洛尔对映体人体葡醛酸化代谢的立体选择性。方法 用生物合成法合成R-（+）-普萘洛尔葡醛酸苷，并经C₁₈固相萃取柱纯化、浓集，得到标准储备液，用于尿中普萘洛尔葡醛苷含量测定，计算药动学参数。结果 R-(+)-普萘洛尔葡醛酸苷与S(-)-普萘洛尔葡醛酸苷的消除速率常数（K）分别为(0.283?3±0.058)与(0.194?6±0.040)h^-1，达峰时(t_max)分别为(1.75±0.33)与(2.21±0.45)h，24 h累积尿药量（X_u）分别为(2.952±0.615)与(5.648±0.977)μmol。结论 人体葡萄糖醛酸转移酶对普萘洛尔光学异构体葡醛酸结合反应的催化作用有立体选择性。

Study on the stereoselectivity of racemic propranolol glucuronidation metabolism

OBJECTIVE A HPLC method was developed to determine directly propranolol glucuronide in urine of healthy volunteers and evaluate the stereoselectivity of racemic propranolol glucuronidation metabolism METHODS The standard for this direct assay was prepared by incubation of liver microsomes with R-(+)-propranolol. The R-(+)-propranolol glucuronide ［R-(+)-PG］ obtained was purified and concentrated with solid-phase extraction. The stock concentration was measured, after enzymatic hydrolysis with β-glucuronidase，by an indirect method. The concentrations of R-(+) and S-(-)-propranolol glucuronide ［S-(-) PG］ in urine were determined and their pharmacokinetic parameters were calculated RESULTS The main pharmacokinetic parameters were as follow: K were (0.283 3±0.058) and(0.194?6±0.040)h^-1, t_max were (1.75±0.33) and (2.21±0.45)h, X_u were (2.952±0.615) and (5.648±0.977)μmol for R-(+)-PG and S-(-)PG respectively CONCLUSION The glucuronidation of racemic propranolol in human has stereoselectivity.