丹红注射液对阿托伐他汀钙在大鼠体内药动学的影响

Effects of Danhong Injection on Pharmacokinetics of Atorvastatin Calcium in Rats

目的:研究丹红注射液对阿托伐他汀钙(ATV)在大鼠体内药动学的影响。方法:以盐酸噻氯匹定为内标,采用超高效液相色谱-串联质谱法测定大鼠血浆中ATV的药物浓度。色谱柱为Acquity^(TM)BEH C_(18),流动相为5 mmol/L甲酸铵溶液(含0.1%甲酸)-甲醇(梯度洗脱);离子源为电喷雾离子源,采用多反应离子监测(MRM)模式,质荷比(m/z)分别为559.20→440.20(ATV)、264.20→154.05(内标)。将24只SD大鼠随机分为ATV单用组(单独给予ATV,10 mg/kg)和丹红注射液低、中、高剂量联用组(给予丹红注射液1、2、4 mL/kg+ATV 10 mg/kg),分别于不同时间点取血,测定ATV血药浓度并计算其药动学参数。结果:ATV的血药浓度线性范围为0.25～62.50 ng/mL,定量下限为0.25 ng/mL;精密度、稳定性试验的RSD均小于15%;提取回收率、基质效应均大于85%。丹红注射液中、高剂量联用组ATV的c_(max)分别为(23.78±6.40)、(33.66±8.15)ng/mL,显著高于ATV单用组的(13.99±2.54)ng/mL(P<0.05);丹红注射液低、中、高剂量联用组ATV的AUC_(0-24 h)分别为(67.20±15.22)、(88.16±14.84)、(126.84±31.55)ng·h/mL,显著高于ATV单用组的(46.08±7.47)ng·h/mL(P<0.05或P<0.01)。结论:丹红注射液联合给药可显著增加ATV在大鼠体内的暴露量。

OBJECTIVE:To study the effects of Danhong injection on the pharmacokinetics of atorvastatin calcium(ATV)in rats.METHODS:The plasma concentration of ATV in rats was determined by UPLC-MS/MS using hydrochloric piperidine as internal standard.The determination was performed on AcquityTM BEH C18 column with mobile phase consisted of 5 mmol/L ammonium formate solution(containing 0.1%formic acid)-methanol(gradient elution).The ion source was ESI,and the mass transfer ratio(m/z)was 559.20→440.20(ATV)and 264.20→154.05(internal standard)by multiple reaction monitoring(MRM)mode.A total of 24 SD rats were randomly divided into ATV alone group(ATV,10 mg/kg),Danhong injection low-dose,medium-dose and high-dose groups(Danhong injection 1,2,4 mL/kg+ATV 10 mg/kg).Blood samples were collected at different time points,and plasma concentration was determined and pharmacokinetic parameters of ATV were calculated.RESULTS:The linear range of ATV was 0.25-62.50 ng/mL,and the limit of quantitation was 0.25 ng/mL.RSDs of precision and stability tests were all lower than 15%.Extraction recovery and matrix effect were all higher than 85%.The pharmacokinetic parameter cmax of ATV in Danhong injection medium-dose and high-dose groups were(23.78±6.4),(33.66±8.15)ng/mL,which were significantly higher than(13.99±2.54)ng/mL in ATV alone group(P<0.05).AUC0-24 h of Danhong injection low-dose,medium-dose and high-dose groups were(67.20±15.22),(88.16±14.84),(126.84±31.55)ng·h/mL,which were significantly higher than(46.08±7.47)ng·h/mL in ATV alone group(P<0.05 or P<0.01).CONCLUSIONS:Combined administration of Danhong injection can significantly increase the plasma exposure of ATV in rats.