苯溴马隆对格列美脲及其代谢物羟基格列美脲在大鼠体内药动学的影响

Effect of benzbromarone on pharmacokinetics of glimepiride and its metabolite hydroxy glimepiride in rats

目的研究苯溴马隆(BBR)对大鼠体内格列美脲(GMP)及其代谢物羟基格列美脲(H-GMP)药动学特征的影响。方法 18只健康雄性SD大鼠随机均分3组,对照组、低剂量BBR组和高剂量BBR组,分别每天灌胃等体积的0.5%羧甲基纤维素钠(0.5%CMC-Na)、5.20 mg·kg^(-1) BBR和20.83 mg·kg^(-1) BBR,连续1周,第8天3组给予上述药物2 h后均灌胃1.0 mg·kg^(-1) GMP。分别于给药前和给药后0.166 7、0.5、1、2、3、4、6、8、10和12 h大鼠眼眶取血,血样处理后采用LC-MS/MS检测大鼠血浆中GMP及H-GMP的浓度。结果与对照组相比,低剂量BBR组的GMP及H-GMP药动学参数差异均无统计学意义;而高剂量BBR组的GMP及H-GMP的ρ(max)、ρ(1/2Z)、AUC(0→t)和AUC(0→∞)显著增加,CLz/F显著减少(P<0.05);另外H-GMP的t(max)显著减少(P<0.05)。与低剂量BBR组比较,高剂量BBR组的GMP的ρ(max)、AUC(0→t)和AUC(0→∞)显著增加,CLz/F显著减少(P<0.05);H-GMP的t(1/2Z)和t(max)显著减少(P<0.05)。结论合用低剂量BBR不影响大鼠体内GMP及其代谢物H-GMP的药动学特征,但合用高剂量BBR可改变GMP的代谢。

AIM To evaluate the effects of benzbromarone(BBR) on pharmacokinetics of glimepiride(GMP) and its metabolite hydroxy glimepiride(H-GMP) in rats. METHODS Totally 18 healthy male SD rats were randomly divided into 3 groups and treated with 0.5% CMC-Na, low-dose BBR(5.20 mg·kg-1·d-1) and high-dose BBR(20.83 mg·kg-1·d-1) for one week. The 1.0 mg·kg-1 GMP was administrated 2 h later since administration of 0.5% CMC-Na or BBR. Blood samples were obtained from orbital plexus of rats at the time points of 0.166 7, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 h after administration. Plasma samples were analyzed for GMP and its metabolite H-GMP on a LC-MS/MS system. RESULTS Compared with the control group, the pharmacokinetic parameters of GMP and H-GMP were not statistically significant in the low-dose BBR group. However, high-dose BBR significantly increased the ρmax, t1/2 Z, AUC0→t and AUC0→∞ values and decreased the CLz/F values of GMP and H-GMP(P<0.05). High-dose BBR also decreased the tmax values of H-GMP(P<0.05). Compared with low-dose BBR group, high-dose BBR significantly increased the ρmax, AUC0→t and AUC0→∞ values and decreased the CLz/F values of GMP(P<0.05), and decreased the t1/2 Z and CLz/F values of H-GMP(P<0.05). CONCLUTION Low-dose BBR does not affect GMP and H-GMP pharmacokinetics in rats, while high-dose BBR apparently alters GMP metabolism.