利格列汀凝胶的大鼠体内药动学研究

Study on pharmacokinetic of linagliptin gelin rats in vivo

凝胶剂具有缓释可控、易于涂展和吸收速度快等优点,通过研究利格列汀凝胶剂和口服给药在大鼠体内药动学差异,评估利格利汀凝胶剂的药动学相关特性.雄性SD大鼠随机分为两组,给予利格利汀凝胶(10 mg/kg,以利格利汀计)和利格利汀原药,分别在服药后按时间眼眶取血0.5 mL,利用高效液相色谱法测定不同时间点血浆中利格列汀含量,通过PK solver 2.0软件进行药动学数据分析,口服给药组血浆中主要药动学参数Cmax为983.212±32.263 ng/mL,Tmax为1.5 h,AUC(0-t)为5731.935±265.959 ng/mL*h,MRT为30.415±5.310 h,t1/2为29.077±4.847 h;凝胶给药组的药动学参数Cmax为863.011±66.053 ng/mL,Tmax为1.5 h,AUC(0-t)为4362.826±142.086 ng/mL*h,MRT为31.370±4.282 h,t1/2为31.231±4.197 h.发现利格利汀凝胶对比口服给药体内滞留时间和半衰期均延长,生物利用度差异不明显,是一种可替代利格列汀口服的良好新制剂,可进一步临床开发提升患者的依从性.

Gel has some advantages of excellent control release,being easy to spread and absorbing rapidly.In the present study,we compared the pharmacokinetics of linagliptin in rats after transdermal administration by gel through the skin and oral administration,to evaluate the pharmacokinetic properties of the linagliptin gel.Male SD rats were randomly divided into 2 groups,one group was given linagliptin gel(10 mg/kg based on linagliptin)and another group was oral administrated linagliptin at a dose of 10 mg/kg.0.5 mL fundus venous plexus blood of each group was taken as samples according to the time points after administration.The plasma concentrations of linagliptin were measured by HPLC at different time points.The data of two groups were analyzed by the PK solver 2.0 system,which presented the main pharmacokinetic parameters for oral administration in the plasma as follows:Cmax=983.212±32.263 ng/mL,Tmax=1.5 h,AUC(0-t)=5731.935±265.959 ng/mL*h,MRT=30.415±5.310 h,t1/2=29.077±4.847 h;the main pharmacokinetic parameters for linagliptin gel group in the plasma:Cmax=863.011±66.053 ng/mL,Tmax=1.5 h,AUC(0-t)=4362.826±142.086 ng/mL*h,MRT=31.370±4.282 h,t1/2=31.231±4.197 h.These results showed that the retention time and half-life of Ligliptin gel were prolonged compared with oral administration,with no obvious difference in bioavailability.The linagliptin gel had potential applications to replace the linagliptin tablet.The formulation of the linagliptin gel could be further developed to improve the patients’compliance.