Non-Clinical Safety, F. Hoffmann-La Roche Ltd., Bldg. 70/127, CH-4070 Basel, Switzerland.
Antimicrob Agents Chemother. 2009 Nov;53(11):4753-61. doi: 10.1128/AAC.01541-08. Epub 2009 Aug 31.
Oseltamivir, a potent and selective inhibitor of influenza A and B virus neuraminidases, is a prodrug that is systemically converted into the active metabolite oseltamivir carboxylate. In light of reported neuropsychiatric events in influenza patients, including some taking oseltamivir, and as part of a full assessment to determine whether oseltamivir could contribute to, or exacerbate, such events, we undertook a series of nonclinical studies. In particular, we investigated (i) the distribution of oseltamivir and oseltamivir carboxylate in the central nervous system of rats after single intravenous doses of oseltamivir and oseltamivir carboxylate and oral doses of oseltamivir, (ii) the active transport of oseltamivir and oseltamivir carboxylate in vitro by transporters located in the blood-brain barrier, and (iii) the extent of local conversion of oseltamivir to oseltamivir carboxylate in brain fractions. In all experiments, results showed that the extent of partitioning of oseltamivir and especially oseltamivir carboxylate to the central nervous system was low. Brain-to-plasma exposure ratios were approximately 0.2 for oseltamivir and 0.01 for oseltamivir carboxylate. Apart from oseltamivir being a good substrate for the P-glycoprotein transporter, no other active transport processes were observed. The conversion of the prodrug to the active metabolite was slow and limited in human and rat brain S9 fractions. Overall, these studies indicate that the potential for oseltamivir and oseltamivir carboxylate to reach the central nervous system in high quantities is low and, together with other analyses and studies, that their involvement in neuropsychiatric events in influenza patients is unlikely.
奥司他韦是一种强效且选择性的流感病毒 A 和 B 型神经氨酸酶抑制剂，是一种前药，在体内被系统转化为活性代谢物奥司他韦羧酸盐。鉴于流感患者报告的神经精神事件，包括一些服用奥司他韦的患者，并且作为全面评估的一部分，以确定奥司他韦是否会导致或加剧此类事件，我们进行了一系列非临床研究。特别是，我们研究了：（i）单次静脉注射奥司他韦和奥司他韦羧酸盐以及口服奥司他韦后，奥司他韦和奥司他韦羧酸盐在大鼠中枢神经系统中的分布；（ii）位于血脑屏障中的转运体对奥司他韦和奥司他韦羧酸盐的主动转运；（iii）奥司他韦在脑部分中的局部转化为奥司他韦羧酸盐的程度。在所有实验中，结果表明，奥司他韦和奥司他韦羧酸盐向中枢神经系统分配的程度较低。奥司他韦的脑/血浆暴露比约为 0.2，奥司他韦羧酸盐约为 0.01。除了奥司他韦是 P-糖蛋白转运体的良好底物外，未观察到其他主动转运过程。前药向活性代谢物的转化速度缓慢且在人和大鼠脑 S9 级分中受到限制。总体而言，这些研究表明，奥司他韦和奥司他韦羧酸盐到达中枢神经系统的可能性较低，并且结合其他分析和研究，它们不太可能参与流感患者的神经精神事件。
