摘要
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.
出处
《中国药房》
CAS
北大核心
2018年第3期307-311,共5页
China Pharmacy
基金
国家自然科学基金资助项目(No.81573793)
上海市临床药学重点专科建设项目(No.2016-40044-002)
关键词
环磷酰胺
五酯胶囊
五味子酯甲
药动学
大鼠
Cyclophosphamide
Wuzhi capsule
Schizander A
Pharmacokinetics
Rats