对羟基苯甲酸及其钠盐在小鼠和食蟹猴体内药代动力学及组织分布研究  

Pharmacokinetics and tissue distribution of p-hydroxybenzoic acid and sodium p-hydroxybenzoate in mice and cynomolgus monkeys

作　　者：杨营营 魏承琼 韦杏淑 王宇晖 段小群[2] YANG Ying-ying;WEI Cheng-qiong;WEI Xing-shu;WANG Yu-hui;DUAN Xiao-qun(School of Pharmacy,Guilin Medical University;School of Biomedical in Dustry,Guilin Medical University,Guilin 541199,China)

机构地区：[1]桂林医学院药学院 [2]桂林医学院生物医药产业学院,桂林541199

出　　处：《天然产物研究与开发》2022年第11期1811-1821,共11页Natural Product Research and Development

基　　金：国家自然科学基金(82160615);广西八桂学者专项(桂财教函[2017]143号)。

摘　　要：前期研究表明对羟基苯甲酸(p-HBA)及其钠盐对羟基苯甲酸钠(s-HBA)均为治疗溃疡性结肠炎的潜在药物。本文研究p-HBA及s-HBA单次给药在正常小鼠体内药代动力学及组织分布特征,以及单次给药s-HBA后食蟹猴体内药代动力学特征。小鼠灌胃给予20 mg/kg的p-HBA和20、50、100 mg/kg的s-HBA,以及食蟹猴灌胃给予4、10、20 mg/kg的s-HBA。LC-MS/MS测定p-HBA和s-HBA在小鼠血浆和组织中的浓度,以及s-HBA在食蟹猴血浆中的浓度。所有血浆和组织均使用乙腈沉淀蛋白法处理。p-HBA及s-HBA在20 mg/kg的剂量下,血浆达峰时间T_(max)分别为0.08、0.08 h,达峰浓度C_(max)分别为20453.98、30683.33 ng/kg,时间曲线下面积AUC_(0-t)分别为7180.27、12008.42 ng·h/mL,半衰期t_(1/2)分别为0.57、0.59 h。s-HBA在小鼠和食蟹猴体内,C_(max)和AUC_(0-t)与剂量均呈良好的线性关系。分别给药p-HBA及s-HBA后,在小鼠的心,肝,脾,肺,肾,脑和结肠组织中均能检测到较高浓度的p-HBA。结果表明,p-HBA及s-HBA灌胃给药后在小鼠和食蟹猴体内吸收和消除均较快,在小鼠体内组织分布广泛,以肾和肝浓度最高,推测其对肾和肝有一定的靶向性,所有组织均无明显蓄积,提示安全性良好。Previous studies have shown that p-hydroxybenzoic acid(p-HBA)and sodium p-hydroxybenzoate(s-HBA)are both potential drugs for the treatment of ulcerative colitis.In this study,the pharmacokinetic and tissue distribution characteristics of p-HBA and s-HBA were studied in normal mice and cynomolgus monkeys after a single administration of s-HBA.Mice were given 20 mg/kg p-HBA and 20,50 and 100 mg/kg s-HBA by intragastric administration,and cynomolgus monkeys were given 4,10,and 20 mg/kg s-HBA by intragastric administration.The concentrations of p-HBA and s-HBA in plasma and tissue of mice and s-HBA in plasma of cynomolgus monkeys were determined by LC-MS/MS.All plasma and tissue samples were treated with acetonitrile precipitated protein method.At the dose of 20 mg/kg,T_(max) of p-HBA and s-HBA was 0.08 and 0.08 h,C_(max) of plasma was 20453.98 and 30683.33 ng/kg,and AUC_(0-t) was 7180.27 and 12008.42 ng·h/mL,t_(1/2) was 0.57 and 0.59 h,respectively.The C_(max) and AUC_(0-t) showed a good linear relationship with dose of s-HBA in mice and cynomolgus monkeys.The high concentration of p-HBA can be detected in the tissues of heart,liver,spleen,lung,kidney,brain and colon of mice after administration of p-HBA and s-HBA.The results showed that p-HBA and s-HBA were quickly absorbed and eliminated in mice and cynomolgus monkeys after oral administration,and were widely distributed in mice tissues,with the highest concentration in kidney and liver.It was speculated that p-HBA had certain targeting property on kidney and liver,and there was no obvious accumulation in all tissues,prompting its good security.

关 键 词：对羟基苯甲酸 对羟基苯甲酸钠 LC-MS/MS 药代动力学 组织分布 食蟹猴 

分 类 号：R285.5[医药卫生—中药学]