氯硝柳胺在小鼠血浆中的代谢及抗日本血吸虫尾蚴侵袭作用

Plasma Metabolism and Protective Effect of Oral Administration of Niclosamide on Schistosoma japonicum Cercarial Invasion in Mice

目的通过观察氯硝柳胺口服后血药浓度变化,了解药物在小鼠血浆中的代谢情况,并对其抗日本血吸虫尾蚴侵袭的效果进行观察。方法将24只雌性昆明小鼠随机分成8组,每组3只。每鼠灌胃给药0.2 ml/20 g,剂量为120 mg/kg体重。于给药后0.25、0.5、1、2、4、8、16和24 h眼眶采血,收集血浆,采用高效液相色谱法(HPLC)测定不同时间点的血药浓度,计算药峰浓度(Cmax)、达峰时间(Tmax)、平均滞留时间(MRT)和消除半衰期(T1/2)等药代动力学参数。另取30只昆明小鼠,随机分成6组,每组5只,分别灌胃给药40、80、120、160和200 mg/kg,余下1组作为对照组。给药1 h后进行尾蚴攻击感染,每鼠(40±2)条。再取35只昆明小鼠,随机分成7组,每组5只,灌胃给药200 mg/kg,余下1组作为对照组。于给药后0.25、1、4、8、12和24 h进行尾蚴攻击感染,每鼠(40±2)条。各组小鼠均于感染后35 d处死,计数体内血吸虫成虫数,计算减虫率。结果 120 mg/kg氯硝柳胺灌胃给药后0.25 h,小鼠血药浓度即达到(0.40±0.28)μg/ml,1 h时达到最大值(0.91±0.34)μg/ml,到2 h时已降至(0.49±0.38)μg/ml,之后继续下降,16 h后趋近于0;MRT为(6.78±1.47)h,T1/2为(6.80±7.05)h。氯硝柳胺不同剂量组35 d后检获虫数与对照组差异均无统计学意义(P>0.05)。200 mg/kg氯硝柳胺给药后0.25 h进行尾蚴攻击,35 d后检获虫数显著少于对照组(P<0.05),减虫率为79.1%,其他各组与对照组间差异无统计学意义(P>0.05)。结论氯硝柳胺灌胃给药后,血药浓度迅速上升,1 h可达到峰值。200 mg/kg氯硝柳胺给药后0.25 h时对尾蚴侵袭有一定抵抗效果。

Objective To study the metabolism of niclosamide in plasma， and the protective effect of its oral administration on Schistosoma japonicum cercarial invasion in mice. Methods Twenty-four female Kunming mice were randomly divided into 8 groups， each with 3 mice. Each mouse was treated orally with 120 mg niclosamide per kilogram of body weight （120 mg/kg）. The plasma samples were collected at 0.25， 0.5， 1， 2， 4， 8， 16， and 24 h after treatment by retro-orbital blood sampling. The blood drug concentration was determined by HPLC. The pharmacokinetics parameters were calculated such as peak concentration（Cmax）， peak time（Tmax）， mean residence time（MRT）， and elimination half life（T1/2）. Thirty Kunming mice were randomly divided into 6 groups. Among them， 5 groups were treated orally with 40， 80， 120， 160， and 200 mg/kg niclosamide， respectively. The remaining untreated group served as control. One hour post-treatment， each mouse was infected with 40±2 Schistosoma japonicum cercariae. Another 35 mice treated with 200 mg/kg niclosamide were randomly divided into 7 groups. Mice in each group were infected with 40±2 S. japonicum cercariae on 0.25， 1， 4， 8， 12， and 24 h after treatment， named as group A， B， C， D， E， and F. Five untreated mice served as control（group G）. All mice were sacrificed 35 days post-infection. Mean worm burden and worm reduction were calculated. Results At a dose of 120 mg/kg niclosamide， the blood drug concentration was （0.40±0.28） μg/ml at 0.25 h post-treatment， reached a peak of （0.91±0.34） μg/ml at 1 h， and decreased to （0.49±0.38） μg/ml at 2 h， and got close to 0 at 16 h. The mean residence time（MRT） in mice was （6.78±1.47） h， and the elimination half time was （6.80±7.05） h. No significant difference was found in worm burden between different dose groups and control group（P＞0.05）. The mean worm burden in group A was significantly lower than that of the control （P＜0.05） with a mean worm reduction of 79.1%. And there was no significant difference in worm burden between other groups and the control（P＞0.05）. Conclusions The blood drug concentration increases rapidly by gavage administration of 120 mg/kg niclosamide， reaching to the maximum concentration at 1 h post-treatment. It shows a certain potective effect of oral administration of 200 mg/kg niclosamide on Schistosoma japonicum cercarial invasion at 0.25 h after treatment.