五酯胶囊/五味子酯甲和环磷酰胺联合给药对大鼠体内环磷酰胺药动学的影响研究

Effects of Wuzhi Capsule/Schisantherin A Combined with Cyclophosphamide on the Pharmacokinetics of Cyclophosphamide in Rats

目的:研究五酯胶囊(WZC)/五味子酯甲(Sch A)和环磷酰胺联合给药对大鼠体内环磷酰胺(CTX)药动学的影响。方法:36只大鼠随机分为CTX组(尾静脉注射CTX溶液300 mg/kg),CTX+WZC组(灌胃五酯胶囊300 mg/kg+尾静脉注射CTX溶液300mg/kg),CTX+Sch A低、中、高、极高剂量组(灌胃Sch A 30、300、3 000、30 000μg/kg+尾静脉注射CTX溶液300 mg/kg),每组6只。分别于给药前及给药后0.083、0.25、0.5、1、2、3、4、6、8、12、24、36、48 h自眼眶静脉丛取血0.3 m L,采用超高效液相色谱-串联质谱法测定大鼠血浆中CTX及其代谢产物[脱氯乙基环磷酰胺(DC-CTX)、4-酮基环磷酰胺(4-keto CTX)、羧基磷酰胺(CPM)]的质量浓度,绘制药-时曲线,并用DAS 2.0软件拟合药动学参数。结果:CTX组,CTX+WZC组,CTX+Sch A低、中、高、极高剂量组大鼠血浆中DC-CTX的c_(max)分别为(22 167.85±2 844.93)、(10 920.53±1 490.89)、(18 951.29±1 558.81)、(18 622.08±791.19)、(18 515.20±2 560.61)、(15 133.21±1 305.07)μg/m L,AUC_(0-48 h)分别为(173 864.01±65 342.21)、(100 996.98±33 530.02)、(137 028.16±45 975.19)、(131 650.18±53 196.41)、(113 699.40±34 131.36)、(110 773.27±30 307.15)μg·m L/h;与CTX组比较,CTX+WZC组,CTX+Sch A低、中、高、极高剂量组大鼠血浆中DC-CTX的c_(max)分别降低50.74%、14.51%、16.10%、16.48%、31.73%,AUC_(0-48 h)分别降低约42.23%、21.45%、24.63%、33.37%、36.55%,差异均有统计学意义(P<0.05),t_(1/2)、t_(max)等其余药动学指标无明显变化。结论:WZC与Sch A均可在一定程度上降低DC-CTX的生成,表明二者可以抑制CTX毒性代谢途径进而减少毒性代谢产物氯乙醛的生成;但Sch A对毒性代谢途径的抑制作用弱于WZC,且不存在剂量依赖性。

OBJECTIVE：To study the effects of Wuzhi capsule/schisantherin A（Sch A）combined with cyclophosphamide on the pharmacokinetics of cyclophosphamide（CTX）in rats.METHODS：A total of 36 rats were randomly divided into CTX group（via tail vein,iv,CTX solution 300 mg/kg）,CTX＋WZC group（ig,Wuzhi capsule 300 mg/kg＋via tail vein,iv,CTX solution 300mg/kg）,CTX＋Sch A low-dose,medium-dose,high-dose and excessive high-dose groups（ig,Sch A 30,300,3 000,30 000μg/kg＋via tail vein,iv,CTX solution 300 mg/kg）with 6 rats in each group.Blood samples were collected from orbital venous plexus of rats before medication and 0.083,0.25,0.5,1,2,3,4,6,8,12,24,36,48 h after medication.UPLC-MS/MSmethod was applied for concentration determination of CTX and its metabolites[de-chloroethyl CTX（DC-CTX）,4-ketone CTX（4-keto CTX）,carboxyl phosphamide（CPM）]in plasma of rats.The plasma concentration-time curve was obtained.The pharmacokinetic parameters were fitted by using DAS 2.0 software.RESULTS：The maximum plasma concentration（c_（max））of DC-CTX in CTX group,CTX＋WZC group,CTX＋Sch A low-dose,medium-dose,high-dose and excessive high-dose groups were（22 167.85±2 844.93）,（10 920.53±1 490.89）,（18 951.29±1 558.81）,（18 622.08±791.19）,（18 515.20±2 560.61）,（15 133.21±1 305.07）μg/m L,respectively;the area under the curves（AUC_（0-48 h））were（173 864.01±65 342.21）,（100 996.98±33 530.02）,（137 028.16±45 975.19）,（131 650.18±53 196.41）,（113 699.40±34 131.36）,（110 773.27±30 307.15）μg·m L/h,respectively.Comparedwith CTX group,c_（max）of DC-CTX in CTX group,CTX＋Sch A low-dose,medium-dose,high-dose and excessive high-dose groups were decreased by 50.74%,14.51%,16.10%,16.48%,31.73%,respectively.AUC_（0-48 h）were decreased by about 42.23%,21.45%,24.63%,33.37%,36.55%,respectively;with statistical significance（P〈0.05）.The pharmacokinetic indexes as t_（1/2）,t_（max） had no significant change.CONCLUSIONS：To some degree,both WZC and Sch A can reduce the generation of DC-CTX,which indicates both of them can inhibit CTX toxicity metabolism pathway so as to reduce the generation of toxic metabolite chloroacetaldehyde.The inhibitory effect of Sch A on toxicity metabolism pathway is weaker than that of WZC,and does not have a dose-dependent inhibitory effect.