Biodistribution and metabolism of the anti-influenza drug [11 C]oseltamivir and its active metabolite [11 C]Ro 64-0802 in mice

Abstract Introduction Oseltamivir phosphate (Tamiflu) is an orally active anti-influenza drug, which is hydrolyzed by esterase to its carboxylate metabolite Ro 64-0802 with potent activity to inhibit the influenza virus. The abnormal behavior and death associated with the use of oseltamivir have developed into a major problem in Japan where Tamiflu is often prescribed for seasonal influenza. It is critical to determine the amount of oseltamivir and Ro 64-0802 in the human brain and to elucidate the relationship between their amounts and neuropsychiatric side effects. The aim of this study was to evaluate [11 C]oseltamivir and [11 C]Ro 64-0802 in mice as promising positron emission tomography (PET) ligands for measuring their amounts in living brains. Methods Whole-body biodistribution of [11 C]oseltamivir and [11 C]Ro 64-0802 was determined in mice using the dissection method and micro-PET. In vitro and in vivo metabolite assay was performed in the plasma and brain of mice. Results Between 1 and 60 min after injection of [11 C]oseltamivir and [11 C]Ro 64-0802, 0.20–0.06% and 0.39–0.03% ID/g were detected in the mouse brains, respectively (dissection method). Radioactivity concentrations in the living brains between 0 and 90 min after injection were measured at standardized uptake values of 0.25–0.05 for [11 C]oseltamivir and 0.38–0.02 for [11 C]Ro 64-0802 (micro-PET). In vivo metabolite assay demonstrated the presence of [11 C]oseltamivir and [11 C]Ro 64-0802 in the brains after [11 C]oseltamivir injection. Conclusion This study determined the distribution and metabolism of [11 C]oseltamivir and [11 C]Ro 64-0802 in mice. PET could be used to measure their amounts in the living brain and to elucidate the relationship between the amounts in the brain and the side effects of Tamiflu in the central nervous system.