氢溴酸西酞普兰鼻用温敏凝胶剂在大鼠体内的药代动力学研究

Pharmacokinetics of citalopram hydrobromide thermosensitive nasal gel in rats

目的研究氢溴酸西酞普兰(CTH)鼻用温敏凝胶剂在大鼠体内的药代动力学。方法用高效液相色谱法测定大鼠血中CTH浓度。测定条件:色谱柱为WondasilC18柱(250 mm×4.6 mm,5μm),流动相为乙腈-10 mmol·L-1磷酸二氢钠溶液(pH=5.0,35∶65),检测波长为239 nm,内标为盐酸多奈哌齐。按照体重将大鼠随机分为2组:实验组和对照组,每组6只。实验组鼻腔给予CTH鼻用温敏凝胶剂,对照组灌胃给予0.05%CTH溶液,剂量均为2.5 mg·kg-1。用3P97药代动力学软件求得主要药代动力学参数。结果实验组和对照组的主要药代动力学参数如下。t max分别为(0.10±0.04)和(0.79±0.10)h;Cmax分别为(2127.16±66.68)和(576.84±24.18)ng·mL-1;Ka分别为(9.33±5.06)和(2.36±0.43)h-1;AUC0-t分别为(1818.79±201.47)和(1170.83±239.36)ng·h·mL-1;AUC0-∞分别为(1970.81±194.21)和(1215.86±244.37)ng·h·mL-1。实验组和对照组比较,t max明显减小,Cmax、Ka、AUC0-t以及AUC0-∞均明显增大,差异均有统计学意义(P<0.05或P<0.01)。CTH鼻用温敏凝胶剂的相对生物利用度(Fr)为167.75%。结论CTH鼻用温敏凝胶剂在体内吸收迅速、生物利用度高且给药方便,是一种有潜在应用价值的非口服给药新剂型。

Objective To study the pharmacokinetics of citalopram hydrobromide(CTH)thermosensitive nasal gel in rats.Methods The concentrations of CTH in rat plasma were determined by high performance liquid chromatography.Chromatographic analysis was achieved on a Wondasil C18 reversed phase column(250 mm×4.6 mm,5μm).The mobile phase consisted of acetonitrile and 10 mmol·L-1 sodium dihydrogen phosphate solution(pH=5.0,35∶65)and the detection wavelength was set at 239 nm.Donepezil hydrochloride was used as internal standard.The rats were randomly divided into two groups:experimental group and control group,with 6 rats each group.CTH thermosensitive nasal gel were intranasaly administered to experimental group and the drug aqueous solution given intragastrically to control group,dose was both 2.5 mg·kg-1.The main pharmacokinetic parameters of CTH in two groups were calculated by 3 P97 pharmacokinetic programme.Results The main pharmacokinetic parameters of CTH for experimental group and control group were as follows:tmaxwere(0.10+0.04)and(0.79+0.10)h,Cmaxwere(2127.16+66.68)and(576.84+24.18)ng·mL-1,Kawere(9.33±5.06)and(2.36±0.43)h-1,AUC0-twere(1818.79±201.47)and(1170.83±239.36)ng·h·mL-1,AUC0-∞were(1970.81±194.21)and(1215.86±244.37)ng·h·mL-1,respectively.Compared with control group,tmaxfor experimental group was obviously reduced;however,Cmax,Ka,AUC0-tand AUC0-∞for experimental group were evidently increased.There was significant difference in tmax,Cmax,Ka,AUC0-tand AUC0-∞between experimental and control groups(P<0.05 or P<0.01).The relative bioavailability(Fr)of the drug thermosensitive nasal gel was found to be 167.75%.Conclusion CTH thermosensitive nasal gel is a new non-oral dosage form with potential application value due to rapid in vivo absorption,high bioavailability and convenient use.