塔拉萨敏的抗炎镇痛活性评价及体内处置研究

Study of Anti-inflammatory and Analgesic Activity of Talatisamine and Its Disposition In Vivo

目的探讨塔拉萨敏(Talatisamine)的抗炎镇痛活性和体内处置特征。方法采用λ角叉菜胶致急性炎症模型评价塔拉萨敏的抗炎活性,醋酸致痛扭体模型和红外热板致痛模型评价塔拉萨敏的镇痛活性。C57BL/6J小鼠分别静脉注射1 mg·kg^(-1)或灌胃10 mg·kg^(-1)塔拉萨敏,采集血浆、组织、尿液和粪便样品,用超高效液相色谱与质谱联用(UHPLC-MS/MS)技术分析塔拉萨敏在小鼠体内的处置特征。结果与生理盐水组相比,塔拉萨敏能显著降低小鼠的足跖肿胀率(P<0.05,P<0.01或P<0.001);显著减少小鼠的疼痛扭体次数(P<0.001);显著增加小鼠的痛阈值(P<0.001)。小鼠静脉注射1 mg·kg^(-1)塔拉萨敏后,t_(1/2)为75.61 min,AUC_(0-t)为91.77 min·μmol·L^(-1)。小鼠灌胃10 mg·kg^(-1)塔拉萨敏后,t_(max)为16.00 min,C_(max)为6.38μmol·L^(-1),AUC_(0-t)为763.45 min·μmol·L^(-1),t_(1/2)为84.63 min。塔拉萨敏在小鼠体内的口服生物利用度为83.84%;在组织中分布广泛,尤其在肾和脾脏中分布较多;其消除快,在尿液和粪便中24 h的累计排泄率分别为40.95%和0.89%。结论塔拉萨敏抗炎镇痛活性显著,生物利用度高,吸收快,组织分布广泛,排泄快。

Objective To explore the anti-inflammatory and analgesic effects of Talatisamine,and examine its in vivo disposition characteristics.Methods The anti-inflammatory effect was determined by theλ-carrageenan-induced paw edema model.The analgesic effect was investigated by acetic acid-induced pain model and infrared hot-plate test.C57BL/6J mice were injected intravenously with Talatisamine 1 mg·kg^(-1)or given orally with Talatisamine 10 mg·kg^(-1).Plasma,tissues,urine,and fecal samples were collected for UHPLC-MS/MS analysis to examine disposition characteristics of Talatisamine in mice.Results Compared with the saline group,paw edema rate of mice decreased significantly(P<0.05,P<0.01 or P<0.001),the writhing times of mice were reduced obviously(P<0.001),and pain thresholds of mice increased obviously(P<0.001)in the Talatisamine-treated groups.After intravenous injection of 1 mg·kg^(-1)Talatisamine,the t_(1/2)of Talatisamine in mice was 75.61 min,and the AUC_(0-t)was91.77 min·μmol·L^(-1).After oral administration of 10 mg·kg^(-1)Talatisamine,it was rapidly absorbed into the plasma with t_(max)of 16.00 min,C_(max)of 6.38μmol·L^(-1),AUC_(0-t)of 763.45 min·μmol·L^(-1),and t_(1/2)of 84.63 min.The absolute oral bioavailability of Talatisamine was 83.84%.Talatisamine was widely distributed in tissues,and especially in kidney and spleen.Moreover,Talatisamine was eliminated most rapidly.The cumulative 24 h excretion rates of Talatisamine in urine and feces were 40.95%and 0.89%,respectively.Conclusion Talatisamine has significant anti-inflammatory and analgesic effects as well as high absolute bioavailability.It is rapidly absorbed,widely distributed in tissues,and quickly eliminated in mice.