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Evidence-Based Complementary and Alternative Medicine
Volume 2015, Article ID 917670, 11 pages
Research Article

The Inhibitory Effect of Kakkonto, Japanese Traditional (Kampo) Medicine, on Brain Penetration of Oseltamivir Carboxylate in Mice with Reduced Blood-Brain Barrier Function

1Faculty of Pharmaceutical Sciences, Josai International University, 1 Gumyo, Togane, Chiba 283-8555, Japan
2Faculty of Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan
3Onko-Do Kampo Akebono Yakkyoku Co., Ltd., 1-3-10 Gakuenhigashi-cho, Kodaira, Tokyo 187-0043, Japan

Received 30 September 2014; Revised 30 January 2015; Accepted 31 January 2015

Academic Editor: Nobuo Yamaguchi

Copyright © 2015 Kousuke Ohara et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Oseltamivir phosphate (OP) is used to treat influenza virus infections. However, its use may result in central nervous system (CNS) adverse effects. In Japan, OP is used with Kampo formulations to improve clinical effectiveness. We evaluated the potential for using Kampo formulations to reduce CNS adverse effects by quantifying the CNS distribution of oseltamivir and its active metabolite oseltamivir carboxylate (OC) when administered with maoto and kakkonto. We administered lipopolysaccharide (LPS) by intraperitoneal injection to C57BL/6 mice to reduce blood-brain barrier function. Saline, maoto, and kakkonto were administered orally at the same time as LPS. OP was orally administered 4 hours after the last LPS injection and the migration of oseltamivir and OC was examined. Additionally, we examined the brain distribution of OC following intravenous administration. Changes in OC concentrations in the brain suggest that, in comparison to LPS-treated control mice, both Kampo formulations increased plasma levels of OC, thereby enhancing its therapeutic effect. Additionally, our findings suggest kakkonto may not only improve the therapeutic effect of oseltamivir but also reduce the risk of CNS-based adverse effects. Considering these findings, it should be noted that administration of kakkonto during periods of inflammation has led to increased OAT3 expression.