大鼠在体单向肠灌流模型研究拉米夫定的肠道渗透性  

Intestinal permeability of lamivudine using in-situ single pass intestinal perfusion in rats

作　　者：王虎斌 黄卫胤 温玉发 孙玲[1] 陈爽 乔红群[2] WANG Hubin;HUANG Weiyin;WEN Yufa;SUN Ling;CHEN Shuang;QIAO Hongqun(Center for Safety Evaluation of Drugs,Jiangsu Provincial Institute of Materia Medica,Nanjing Tech University,Nanjing 211800,China;School of Pharmaceutical Sciences,Nanjing Tech University,Nanjing 211800,China)

机构地区：[1]南京工业大学江苏省药物研究所安全性评价中心,江苏南京211800 [2]南京工业大学药学院,江苏南京211800

出　　处：《南京工业大学学报（自然科学版）》2021年第4期540-546,共7页Journal of Nanjing Tech University(Natural Science Edition)

摘　　要：使用大鼠在体单向肠灌流模型研究拉米夫定的肠道渗透性,用于判断在生物药剂学分类系统(BCS)中拉米夫定的渗透性类别。在该模型上,用高渗透性药物苯妥英钠和低渗透性药物阿昔洛韦作为系统对照,建立并验证高效液相色谱紫外(HPLC UV)检测法分离检测拉米夫定的分析方法。将3种质量浓度(12、120、1200μg/mL)的拉米夫定以0.2 mL/min的灌流速率进行大鼠在体肠道灌流研究。结果表明:拉米夫定在0.25~25μg/mL的质量浓度范围内保持良好的线性关系(相关系数R^(2)=0.9999),且批内、批间精密度和回收率及拉米夫定在不同介质中的稳定性均符合要求;苯妥英钠和阿昔洛韦的有效渗透性系数(P_(eff))分别为(5.26±1.41)×10^(-5)和(0.282±0.208)×10^(-5) cm/s(x±s,n=6);不同剂量组拉米夫定(12、120、1200μg/mL)在大鼠肠道内的P_(eff)分别为(1.44±0.32)×10^(-5)、(1.39±0.37)×10^(-5)、(1.48±0.39)×10^(-5) cm/s(x±s,n=6)。由此可见,拉米夫定在肠道内的吸收介于高、低渗透性对照药物之间,属于BCS分类中的中渗透性药物。剂量组间和不同灌流时间点的肠道吸收参数无显著性差异(P>0.05),表明拉米夫定肠道吸收存在被动扩散机制。To study intestinal permeability of lamivudine for application in permeability classification of lamivudine under biopharmaceutical classification system(BCS),in-situ single pass intestinal perfusion was performed in rats.High-permeability drug phenytoin sodium and low-permeability drug acyclovir were selected as system controllings.A high performance liquid chromatography-ultraviolet detection(HPLC-UV)method was developed and validated for detection of lamivudine.Perfusion was performed at a flow rate of 0.2 mL/min in rats intestine using three concentrations of lamivudine(12,120,1200μg/mL).Results showed that lamivudine maintained a good linear relationship with concentration under the concentration range of 0.25-25μg/mL(R^(2)=0.9999),Precision of intra and inter batch,recovery and stability of lamivudine in different medium were all in accordance with requirement of detection.In addition,the effective permeability coefficient(P_(eff))of phenytoin sodium and acyclovir was(5.26±1.41)×10^(-5) and(0.282±0.208)×10^(-5) cm/s(x±s,n=6),respectively.P_(eff) of lamivudine with different mass concentration(12,120 and 1200μg/mL)in rats intestine was(1.44±0.32)×10^(-5),(1.39±0.37)×10^(-5) and(1.48±0.39)×10^(-5) cm/s(x±s,n=6).Thus,the absorption of lamivudine in intestine was between high-permeability and low-permeability model drug,which was a medium-permeability drug in the BCS classification.There was no significant difference in intestinal absorption parameter between different dose groups and different perfusion time points(P>0.05),suggesting that lamivudine exhibited the mechanism of passive diffusion in intestinal absorption.

关 键 词：拉米夫定 在体单向肠灌流模型 肠道吸收 有效渗透性系数 

分 类 号：R917[医药卫生—药物分析学]