CYP2D6抑制剂对艾瑞昔布大鼠体内药代动力学的影响

目的考察CYP2D6抑制剂帕罗西汀对艾瑞昔布在大鼠体内药代动力学的影响。方法选用甲苯磺丁脲为内标,色谱柱为Diamonsil C18柱(150 mm×4.6 mm,5μm),流动相为甲醇-水-甲酸(85∶15∶0.1,V/V/V),等度洗脱,流速为1.0 mL/min,柱温为30℃。将40只健康雄性SD大鼠随机分为实验组和对照组,各20只,实验组大鼠灌胃帕罗西汀溶液2 mg/kg,对照组大鼠灌胃等量1‰羧甲基纤维素溶液,1次/日,连续给予7 d。两组大鼠均于第8天灌胃艾瑞昔布灌胃液(20 mg/kg),并按时取血,测定血药浓度,采用DAS 2.1.1软件拟合药-时曲线(AUC),并计算药代动力学参数,采用SPSS 13.0统计学软件分析。结果实验组的0-∞药时曲线下面积(AUC0-∞)为(1730.4±606.5)mg/(h·L)明显高于对照组的(1331.3±592.6)mg/(h·L)(P<0.05);实验组的峰浓度(Cmax)为(192.1±70.8)mg/L,明显高于对照组的(162.2±53.0)mg/L(P<0.05);实验组的清除率(CL)为(0.01±0.01)L/(kg·h),明显优于对照组的(0.02±0.01)L/(kg·h)(P<0.05)。结论CYP2D6抑制剂帕罗西汀预处理的大鼠,其体内艾瑞昔布的暴露量增大,清除率减小。CYP2D6抑制剂减慢了艾瑞昔布在大鼠体内的代谢,推断CYP2D6参与了艾瑞昔布的代谢。

Effect of an Inhibitor of CYP2D6 on the Pharmacokinetic of Imrecoxib in Rats

Objective To study the effect of CYP2D6 on the pharmacokinetic of imrecoxib in rats.Methods Tolbutamide was selected as the internal standard.The samples were separated on a chromatographic column of Diamonsil C18(150 mm×4.6 mm,5μm)and a mobile phase consisting of acetonitrile-water-formic acid(85∶15∶0.1,V/V/V)was used at a flow rate of 1.0 mL/min and a column temperature of 30℃.Forty healthy male SD rats were randomly divided into the test group and control group,20 in each group.The test group were pretreated with paroxetine(2 mg/kg)and the control group with the same dosage of 1‰carboxymethylcellulose,once a day,for consecutive 7 days,respectively.On day 8,imrecoxib was administered orally at a dose of 20 mg/kg to all rats.Blood samples from plexus venous at fundus oculi were collected and detected.The Area Under Curve(AUC)and pharmacokinetics were calculated with DAS 2.1.1 software and analyzed with SPSS 13.0 software.Results AUC0-∞of imrecoxib in the test group was(1730.4±606.5)mg/(h·L),which was significantly higher than(1331.3±592.6)mg/(h·L)in the control group(P<0.05).Cmax in the test group was(192.1±70.8)mg/L,which was significantly higher than(162.2±53.0)mg/L in the control group(P<0.05).Clearance rate(CL)in the test group was(0.01±0.01)L/(kg·h),which was significantly higher than(0.02±0.01)L/(kg·h)in the control group(P<0.05).Conclusion The metabolism of imrecoxib is slowed down in rats pretreated with paroxetine with increased exposure and decreased clearance.We infer that CYP2D6 is involved in the metabolism of imrecoxib.