黄芩苷与甘草酸对恩诺沙星在异育银鲫体内代谢的影响

将黄芩苷(baicalin,BL)和甘草酸(glycyrrhizin,GZ)口灌异育银鲫(Carassius auratus gibelio),探讨其对恩诺沙星(enrofloxacin,ENR)在体内的代谢和肝微粒体细胞色素氧化酶CYP1A、CYP3A活性的影响。异育银鲫连续7 d分别口灌黄芩苷(100 mg/kg)和甘草酸(100 mg/kg),以口灌玉米油作为对照。末次给药24 h后每组随机取10尾腹腔注射恩诺沙星(10 mg/kg),采用单个动物连续采血,HPLC测定血浆恩诺沙星和其代谢产物环丙沙星(cipmfloxacin,CIP)浓度,分析药动学及其参数;同时每组选取6尾检测肝微粒体CYP1A和CYP3A活性。结果表明:(1)黄芩苷(BL)和甘草酸(GZ)对恩诺沙星的吸收有明显抑制作用,主要表现在恩诺沙星峰浓度(Cmax)降低,曲线下面积(AUC)减少;(2)口灌BL和GZ后,恩诺沙星及其代谢产物环丙沙星的消除半衰期(t1/2z)明显小于对照组(P<0.05),而总体清除率(CLz/F)则增大,说明黄芩苷和甘草酸促进了恩诺沙星和环丙沙星的消除;(3)口灌BL和GZ后,BL组和GZ组的Cmax-CIP/Cmax-ENR比值分别为1.48%、2.22%,对照为0.95%;BL组和GZ组的AUC0-t-CIP/AUC0-t-ENR比值分别为2.16%、1.76%,对照组为1.7%。综合分析代谢产物环丙沙星峰浓度、Cmax-CIP/Cmax-ENR和AUC0-t-CIP/AUC0-t-ENR比值可以得出,黄芩苷和甘草酸对恩诺沙星N-脱乙基具有诱导作用;(4)与对照组相比较,BL组和GZ组的7-乙氧基异吩唑酮-O-脱乙基酶(EROD,CYP1A标志酶)和红霉素-N-脱甲基酶(ERND,CYP3A标志酶)活性显著升高(P<0.05),说明黄芩苷和甘草酸对CYP1A和CYP3A都有诱导作用。结合以上结果,认为黄芩苷和甘草酸加速了恩诺沙星的消除和其代谢产物CIP的生成,很可能与诱导CYP1A和CYP3A活性有关。

Effect of baicalin and glycyrrhizin on enrofloxacin in vivo in crucian carp (Carassius auratus gibelio)

Cytochrome P450s(CYPs) widely distribute in the liver of aquatic organisms and play a key role in drug metabolism.CYPs catalyze the N-deethylation of Enrofloxacin(ENR) to Ciprofloxacin(CIP).However,there is limited information regarding the action of CYPs in ?sh.We evaluated the metabolism of ENR following oral administrated of baicalin(100 mg/kg) and glycyrrhizin(100 mg/kg) in crucian carp,Carassium auratus gibelio.We measured the enzymatic activity of cytochrome P450 1A(CYP1A) and 3A(CYP3A) in liver microsomes.In addition,we documented the pharmacokinetics of ENR by continuous blood sampling.The absorption of ENR decreased significantly over time and both Cmax and AUC also deceased.AUC and t1/2z decreased signficantly whereas CL inceased after oral administrated of baicalin and glycyrrhizin,suggesting that ENR elimination was accelerated.The Cmax CIP/Cmax ENR was 1.48% and 2.22% for the BL and GZ groups,respectively(control: 0.95%).The AUC0-t-CIP/AUC0-t-ENR was 2.16% and 1.76% for the BL and GZ groups,respectively(control: 1.7%).Thus,BL and GZ contributed to induce N-deethylation of ENR.Pretreatment with BL and GZ was associated with a significant(P<0.05) incease in ethoxyresorufin-O-deethylation(EROD) and erythromycin-N-demethylation(ERND) activity,the specific probes for CYP1A and CYP3A,respectively.In summary,BL and GZ accelerated the elimination of ENR.Furthermore,production of the ENR metabolite was related to the induction of CYP1A and CYP3A enzymatic activity.