奥扎格雷钠对大鼠CYP2D6亚型酶的影响

目的通过奥扎格雷钠的大鼠体内、外实验,观察奥扎格雷钠对大鼠CYP2D6亚型酶的影响。方法对照组和奥扎格雷钠诱导组大鼠分别经口给予生理盐水和奥扎格雷钠1wk,HPLC法测定大鼠尿样及肝微粒体中CYP2D6的探针药物右美沙芬的代谢率,观察奥扎格雷钠对CYP2D6活性的影响。结果①大鼠给予奥扎格雷钠(37mg·kg-1),其尿样中右美沙芬的代谢率明显高于对照组(P<0·01);②奥扎格雷钠诱导组大鼠肝微粒体中加入右美沙芬(0·324mmol·L-1),其右美沙芬的代谢率明显高于对照组(P<0·01);③奥扎格雷钠与CYP2D6特异性抑制剂西米替丁可明显降低右美沙芬的代谢率(P<0·01),并且奥扎格雷钠组其右美沙芬的代谢率低于西米替丁组(P<0·05);④奥扎格雷钠IC50=26·5μmol·L-1,西咪替丁IC50=86·3μmol·L-1,奥扎格雷钠诱导组肝微粒体Km=0·67mmol·L-1,Vmax=2·13nmol·min-1·g-1protein;对照组肝微粒体Km=0·29mmol·L-1,Vmax=0·91nmol·min-1·g-1protein;⑤体内和体外相应实验数据具有很好的相关性(r=0·9811)。结论奥扎格雷钠可诱导CYP2D6酶的活性。

The influence of soduim ozagrel on rat CYP2D6

Aim To investigate the influence of sodium ozagrel on rat liver CYP2D6 activity in vivo and in vitro, respectively. Methods High-performance liquid chromatography (HPLC) was used to measure metabolism of dextromethorphan (DM) metabolism in rat urine and liver microsomal reconstituted system,which was expressed as DM metabolic rate (DX/DM,DX:dextrophan, metabolites of DM ) and used as a probe to determine the activity of CYP2D6;the effect of sodium ozagrel on rat CYP2D6 was identified by measurement of the rate in vivo and in vitro as well as by the inhibition study. Results ① In vivo, the DM metabolic rate of treated group (sodium ozagrel, 37 mg·kg~ -1 )in rat urine was obviously higher than that of control(P<0.01). ② In vitro, The DM metabolic rate of treated group in rat liver microsomes was obviously higher than that of control (P<0.01). ③ Sodium ozagrel and cimitidine inhibited the dextromethorphan metabolic rate(P<0.01). The DM metabolic rate of cimetidine group was higher than that of ozagrel(P<0.05). ④ Sodium Ozagrel IC_ 50 =26.5 μmol·L~ -1 ,Cimetidine IC_ 50 =86.3 μmol·L~ -1 ,treated group:K_m=0.67 mmol·L~ -1 ,V_ max =2.13 nmol·min~ -1 ·g~ -1 protein;control group:K_m=0.29 mmol·L~ -1 ,V_ max =0.91 nmol·min~ -1 ·g~ -1 protein. ⑤ Do the linear regression of experimental data in vivo and in vitro(r=0.9811).Conclusion Sodium Ozagrel can induce the activity of CYP2D6.