卡培他滨/聚乙二醇1000/蒙脱石复合物在大鼠体内的药动学研究

Study on Pharmacokinetics of Capecitabine/Polyethylene Glycol 1000/Montmorillonite Compound in Rats in vivo

目的：建立测定大鼠卡培他滨（CAP）血药浓度的方法,并用于卡培他滨/聚乙二醇1000/蒙脱石（CAP/PEG1000/MMT）复合物在大鼠体内的药动学研究。方法：采用高效液相色谱（HPLC）法。色谱柱为Kromasil C18,流动相为0.1%冰醋酸-乙腈（73∶27）,流速为1.0 ml/min,检测波长为250 nm,柱温为40℃,进样量为10μl。将18只Wistar大鼠随机分为CAP组、CAP/MMT组（MMT为载体）和CAP/PEG1000/MMT组（PEG1000/MMT为载体）,分别ig给予相当于CAP 200 mg/kg的药物。分别于给药15、30、60、90、120、180、240、300、360 min后取血,分离血浆,加内标阿魏酸,经甲醇沉淀蛋白后,用HPLC法测定其血药浓度,利用3p97软件计算药动学参数。结果：CAP检测质量浓度的线性范围为0.054 9~4.390 0μg/ml（r=0.998 2）;方法回收率为98.2%~102.1%（RSD为1.50%~3.29%,n=5）,提取回收率为76.2%~78.9%（RSD为2.29%~2.99%,n=5）。CAP、CAP/MMT和CAP/PEG1000/MMT组的t1/2分别为（1.11±0.32）、（1.57±0.32）、（1.62±0.10）h,cmax分别为（2.91±0.36）、（0.91±0.23）、（0.91±0.14）μg/ml,AUC0-6 h分别为（8.70±1.79）、（3.76±0.27）、（3.73±0.25）μg·h/ml,tmax分别为（0.97±0.20）、（1.55±0.47）、（1.50±0.07）h。CAP/MMT和CAP/PEG1000/MMT组间药动学参数差异无统计学意义（P〉0.05）。结论：建立的方法可靠、简便,可用于CAP/PEG1000/MMT在大鼠体内的药动学研究。MMT和PEG1000/MMT复合物均能使CAP在体内的作用时间延长。

OBJECTIVE：To establish a method of determining the plasma concentration of capecitabine/polyethylene glycol1000/montmorillonite（CAP/PEG1000/MMT）in rats＇ plasma for the study on pharmacokinetics of CAP compound in rats in vivo.METHODS：HPLC was adopted.The determination was performed on Kromasil C18 with mobile phase consisted of 0.1% glacial acetic acid-acetonitrile（73 ∶ 27）,at the flow rate of 1.0 ml/min.The detection wavelength was 250 nm and column temperature was40 ℃.The sample size was 10 μl.18 Wistar rats were randomly divided into CAP group,CAP/MMT group（MMT as carrier）and CAP/PEG1000/MMT group（PEG1000/MMT as carrier）and ig given corresponding drugs,that equal to 200 mg/kg of CAP.Blood sample was respectively taken 15,30,60,90,120,180,240,300 and 360 min after the administration of drugs,and plasma was isolated and added with internal standard ferulic acid.The concentration of the drug in the plasma was determined by HPLC following protein precipitation with methanol,based on which the pharmacokinetic parameters were calculated by 3p97 software.RESULTS：The linear range of CAP was 0.054 9-4.390 0 μg/ml（r=0.998 2）with the method recovery of 98.2%-102.1%（RSD=1.50%-3.29%,n=5） and absolute recovery of 76.2%-78.9%（RSD=2.29%-2.99%,n=5）.In the above-mentioned three groups,t1/2were（1.11±0.32）,（1.57±0.32）and（1.62±0.10）h;cmaxwere（2.91±0.36）,（0.91±0.23）and（0.91±0.14）μg/ml;AUC0-6 hwere（8.70±1.79）,（3.76±0.27）and（3.73±0.25）μg·h/ml;and tmaxwere（0.97±0.20）,（1.55±0.47）and（1.50±0.07）h,respectively.There was no significant difference in the pharmacokinetic parameters between the CAP/MMT group and CAP/PEG1000/MMT group（P〉0.05）.CONCLUSIONS：The method is reliable and simple,and can be used for pharmacokinetic study of CAP/PEG1000/MMT in rats.MMT and PEG1000/MMT compound can prolong CAP acting time in the body.