Koyama K, Takahashi M, Nakai N, Takakusa H, Murai T, Hoshi M, Yamamura N, Kobayashi N, Okazaki O
Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan.
Xenobiotica. 2010 Mar;40(3):207-16. doi: 10.3109/00498250903447691.
CS-8958, a prodrug of laninamivir (R-125489), is currently under development as an inhaled anti-influenza drug. In this study, the pharmacokinetics and disposition of CS-8958 were characterized in rats. After intratracheal administration of 14C-CS-8958, radioactivity was retained over long periods in the target tissues (trachea and lung) as its active metabolite R-125489 - 19.12% of the dose was retained in the lung at 24 h. After intratracheal administration of CS-8958, plasma R-125489 concentration was slowly eliminated, and its half-life (14.1 h) was considerably longer than that after intravenous administration of R-125489. The radioactivity of intratracheally administered 14C-CS-8958 was mainly excreted into the urine (67.5% of dose), and this excretion lasted over long periods. R-125489 accounted for most of the urinary radioactivity recovered after 24 h. These results demonstrated that CS-8958 administered intratracheally to rats was converted/hydrolysed to R-125489 in the target tissues, and that the R-125489 was slowly excreted into the urine via an absorption rate-limiting process. Such distinctive pharmacokinetics attributed to the slow release of R-125489 suggests the potential for a long-acting anti-influenza drug.
CS - 8958是拉尼米韦（R - 125489）的前体药物，目前正作为一种吸入式抗流感药物进行研发。在本研究中，对CS - 8958在大鼠体内的药代动力学和处置情况进行了表征。经气管内给予14C - CS - 8958后，放射性以其活性代谢物R - 125489的形式在靶组织（气管和肺）中长期保留——给药剂量的19.12%在24小时时保留在肺中。经气管内给予CS - 8958后，血浆中R - 125489的浓度缓慢消除，其半衰期（14.1小时）明显长于静脉注射R - 125489后的半衰期。经气管内给予的14C - CS - 8958的放射性主要经尿液排泄（占给药剂量的67.5%），且这种排泄持续很长时间。R - 125489占24小时后回收的尿中放射性的大部分。这些结果表明，经气管内给予大鼠的CS - 8958在靶组织中转化/水解为R - 125489，并且R - 125489通过吸收限速过程缓慢排泄到尿液中。这种归因于R - 125489缓慢释放的独特药代动力学表明其具有成为长效抗流感药物的潜力。
