Basic Study of Drug-Drug Interaction between Memantine and the Traditional Japanese Kampo Medicine Yokukansan.

Takashi Matsumoto,Zenji Kawakami,Kyoji Sekiguchi,Junko Watanabe,Kazushige Mizoguchi,Yasushi Ikarashi,Masahiro Yamamoto

doi:10.3390/molecules24010115

Takashi Matsumoto, Zenji Kawakami + Show 5 more

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https://doi.org/10.3390/molecules24010115

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Abstract

Several basic pharmacokinetic and pharmacological studies were conducted as part of a group of studies to clarify the drug-drug interaction (DDI) between memantine (MEM), a drug used to treat Alzheimer’s disease, and yokukansan (YKS), a traditional Japanese Kampo medicine used to treat behavioral and psychological symptoms of dementia. The pharmacokinetic studies showed that there were no statistically significant differences in MEM concentrations in the plasma, brain, and urine between mice treated with MEM alone and with MEM plus YKS. Regarding candidate active ingredients of YKS, there were also no statistically significant differences in concentrations of geissoschizine methyl ether in the plasma and brain, urine, glycyrrhetinic acid in the plasma, and isoliquiritigenin in the urine, in mice treated with YKS alone or with MEM plus YKS. The pharmacological studies showed that isoliquiritigenin, which has an N-methyl-d-aspartic acid (NMDA) receptor antagonistic effect, did not affect the inhibitory effect of MEM on NMDA-induced intracellular Ca2+ influx in primary cultured rat cortical neurons. Moreover, YKS did not affect either the ameliorative effects of MEM on NMDA-induced learning and memory impairment, or the MEM-induced decrease in locomotor activities in mice. These results suggest that there is probably no pharmacokinetic or pharmacological interaction between MEM and YKS in mice, but more detailed studies are needed in the future. Our findings provide important information for future studies, to clarify the DDI more regarding the efficacy and safety of combined use of these drugs in a clinical situation.

Highlights

IntroductionMedicines Agency in 2002, the U.S Food and Drug Administration in 2003, and the Japanese Ministry of Health, Labour and Welfare (MHLW) in 2011 for the treatment of patients with moderate-to-severe dementia from Alzheimer’s disease [1]
Memantine (MEM) hydrochloride, a therapeutic agent used to treat Alzheimer’s disease, was developed by Merz Pharmaceuticals GmbH in Germany [1], and was approved in the EuropeanMedicines Agency in 2002, the U.S Food and Drug Administration in 2003, and the Japanese Ministry of Health, Labour and Welfare (MHLW) in 2011 for the treatment of patients with moderate-to-severe dementia from Alzheimer’s disease [1]
Animal studies using rats have demonstrated that MEM protects cognitive dysfunction induced by the sequential injection of β-amyloid and ibotenate into the bilateral hippocampus [6], N-methyl-D-aspartic acid (NMDA)-induced impairment of passive avoidance learning and long-term potentiation formation [7], and neurodegeneration induced by β-amyloid [8]

Summary

Introduction

Medicines Agency in 2002, the U.S Food and Drug Administration in 2003, and the Japanese Ministry of Health, Labour and Welfare (MHLW) in 2011 for the treatment of patients with moderate-to-severe dementia from Alzheimer’s disease [1]. Various in vitro tests determined the mechanism of action to be a voltage-dependent, uncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, in which MEM showed low-to-moderate affinity and a fast binding–dissociation rate with the receptor [1]. MEM has ameliorative actions against excessive glutamate-induced neurocytotoxicity. MEM has been reported to modify the progressive symptomatic decline in cognition, function, and behavior in patients with moderate-to-severe Alzheimer’s disease in 12- to 28-week trials [4,5]. High doses of MEM inhibit motor activity [9]

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