奥司他韦在树鼩体内的药动及药效学应用研究

The pharmacokinetics and pharmacodynamics of oseltamivir in tree shrew

目的探讨奥司他韦在树鼩体内的药代动力学参数特征,以及在树鼩体内的抗流感病毒药效作用。方法树鼩经口服磷酸奥司他韦后取血浆用于药代动力学分析,并与人、雪貂、小鼠、大鼠的药代动力学参数比较;树鼩经鼻接种感染人流感病毒A/California/04/2009 H1N1和禽流感病毒H9N2突变株Y280-PB2-E627K,给予奥司他韦治疗,观察鼻腔症状,收集感染后第1,3和5天鼻灌洗液及沉淀分别行病毒TCID50检测和细胞分类计数,检测感染后21 d血清中和抗体滴度。结果奥司他韦在树鼩体内的药代动力学参数为:Cmax:1. 34μg/m L,Tmax:0. 75h,T1/2:2. 03 h,AUC0-12:1. 76 mg·h/liter。奥司他韦对感染A/California/04/2009 H1N1病毒的树鼩鼻腔排毒抑制作用不明显,但高剂量组奥司他韦可明显抑制感染H9N2 Y280-PB2-E627K病毒树鼩第1天的鼻腔排毒,减少第3天鼻灌洗液中细胞总数。感染A/California/04/2009 H1N1病毒后产生的抗体效价明显高于H9N2 Y280-PB2-E627K禽流感病毒的抗体效价,奥司他韦抗病毒治疗对感染同一病毒各组间血清抗体效价无影响。结论奥司他韦在树鼩体内的药代动力学参数不同于人或雪貂等模型动物,但其药物血浆清除半衰期和达峰时间与小鼠相近;药效学方面奥司他韦可有效抑制感染H9N2 Y280-PB2-E627K流感病毒树鼩的鼻腔病毒排毒和炎症反应。

Objective To investigate the pharmacokinetic parameters of oseltamivir and the efficacy of oseltamivir against influenza virus in tree shrews.Methods Tree shrews were orally administered oseltamivir for pharmacokinetic analysis,and then their pharmacokinetic parameters were compared with those of humans,ferrets,mice,and rats reported in the literature.The tree shrews were inoculated with human influenza virus A/California/04/2009 H1N1 or avian influenza virus H9N2 Y280-PB2-E627K intranasally.Oseltamivir was orally administered twice a day for 5 consecutive days.Nasal symptoms of the tree shrews were observed,and the viral titer of nasal lavage was determined on 1,3,and 5 days after inoculation,the cell sedimentation of nasal lavage fluid was classified and counted.After21 days of infection,the tree shrews were executed humanely and the serum antibody titers were determined by hemagglutination inhibition test.Results The pharmacokinetics of oral oseltamivir in tree shrews was as follows:C max 1.34μg/mL,T max 0.75 h,T 1/22.03 h,and AUC 0-12 1.76 mg·h/liter.The viral shedding of tree shrews infected with H9N2 Y280-PB2-E627K virus was clearly inhibited after 1 day in the high-dosage oseltamivir treatment group,however,there was no clear inhibitory effect for A/California/04/2009 H1N1 virus.High-dosage oseltamivir treatment also reduced the nasal lavage fluid cell count of tree shrews infected with H9N2 Y280-PB2-E627K virus.The antibody titer of tree shrews infected with A/California/04/2009 H1N1 virus was significantly higher than that of H9N2 Y280-PB2-E627K avian influenza virus.Conclusions The pharmacokinetic parameters of oseltamivir in tree shrews differ from those in humans and other model animals,such as ferrets,however,the T max and T 1/2 of oseltamivir in tree shrews were similar to those of mice.Oseltamivir can effectively inhibit the shedding of H9N2 Y280-PB2-E627K viruses and alleviate the inflammatory reaction in tree shrew nasal cavity.