苯巴比妥诱导对普萘洛尔对映体葡醛酸化立体选择性的影响

目的:以空白及苯巴比妥(PB)诱导的大鼠肝微粒体作为代谢反应酶源,研究R-( )及S-(-)-普萘洛尔体外葡醛酸化反应的立体选择性,考察酶动力学特性和对映体之间的代谢性相互影响.方法:采用体外孵育法进行底物葡醛酸化反应,高效液相色谱法分离测定普萘洛尔2种对映体葡醛酸化代谢产物.结果:空白及诱导组中,各种浓度下均以R-( )-普萘洛尔为优代谢对映体;与空白组相比,PB诱导组中R-( )、S-(-)-普萘洛尔的最大反应速度均显著增强(P<0.01);R-( )-普萘洛尔与酶的亲和力显著增强(P<0.01),S-(-)-普萘洛尔与酶的亲和力显著降低(P<0.05).结论:普萘洛尔2种对映体葡醛酸结合反应呈立体选择性;2种对映体间在高底物浓度时存在代谢抑制作用.

Effects of microsome enzyme induced by phenobarbarbital on the stereoselectivity of recemic propranolol glucuronidation metabolism

Objective: To study the stereoselectivity of R-( ) and S-(-)-propranololglucuronidation and metabolic interaction between R( )- and S-(-)-propranolol. Methods: A RP-HPLC analytical method was developed for determination of R-( )- and S-(-)-propranolol glucuronide (PG) incubated with rat hepatic microsome induced with phenobarbital (PB). The method was applied to investigate the stereoselectivity metabolism of racemic propranolol glucuronidation in vitro. Results: In control and PB group,the concentration of R-( )-PG produced at different substrates was higher than that of S-(-)-PG. Compared with the control,the V max and Cl int for R( )- and S-(-)-propranolol increased significantly;the K m for R( )-propranolol was elevated,while that for S-(-) propranolol was decreased. Conclusion: There is a stereoselectivity in glucuronidation of propranolol in rat hepatic microsome induced with PB and R-( )-propranolol is preferred. Metabolic interaction between R-( )- and S-(-)-propranolol exists with a concentration-dependent mode.