Comparison of glycyrrhizin content in 25 major kinds of Kampo extracts containing Glycyrrhizae Radix used clinically in Japan

Shinsuke Hisaka,Sayaka Masada,Takashi Hakamatsuka,Rika Kojima,Kumiko Nagata,Momoka Tada,Masato Homma,Mitsuhiko Nose

doi:10.1007/s11418-017-1101-x

Shinsuke Hisaka, Sayaka Masada + Show 6 more

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https://doi.org/10.1007/s11418-017-1101-x

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Abstract

Glycyrrhizae Radix is the most frequently used crude drug in Japan and is prescribed in Kampo medicine for the treatment of a wide range of diseases. The major active ingredient of Glycyrrhizae Radix, glycyrrhizin (GL), has been shown to possess various pharmacological actions, but is also known to cause adverse effects such as pseudoaldosteronism. To avoid the adverse effects of GL, precautions have been indicated on the package inserts of Glycyrrhizae Radix-containing formulas depending on the amount of Glycyrrhizae Radix they contain. However, it remains unknown whether the extraction efficiency of GL from Glycyrrhizae Radix is constant throughout the different combinations of crude drugs in Glycyrrhizae Radix-containing formulas. To confirm the basis of the safety regulation, in this study we comprehensively determined the GL content of 25 major kinds of Kampo extracts compounding Glycyrrhizae Radix. We found that the GL content per daily dosage in all Kampo extracts are generally proportional to the compounding amount of Glycyrrhizae Radix, except in the case of shoseiryuto (Sho-seiryu-To). We also found that Schisandrae Fructus in Sho-seiryu-To decoction caused a lowered pH condition and drastically decreased the extraction efficacy of GL from Glycyrrhizae Radix. Moreover, we were able to confirm that the extraction efficiency of GL from Glycyrrhizae Radix is dependent on the pH value of the extraction solvent. The extraction efficiency of GL in the 25 kinds of Kampo extracts was not constant but it correlates significantly with the pH value of the decoction. Furthermore, the GL contents are well correlated with pseudoaldosteronism incidence data obtained from the Japanese Adverse Drug Event Report (JADER) database on the 25 kinds of Kampo extracts. This suggests that the GL content is a better index to consider to avoid the adverse effects of Glycyrrhizae Radix-containing Kampo formulas.

Highlights

IntroductionSeveral investigators have reported that excessive and/or long-term administration of Glycyrrhizae Radix-containing Kampo medicines and crude drug products or GL alone frequently leads to pseudoaldosteronism [13,14,15], such as peripheral edema [16,17,18], hypokalemia [19, 20] and hypertension [21, 22]
Glycyrrhizae Radix is the most frequently used crude drug in Japan and is defined in the Japanese Pharmacopoeia as the root and stolon of Glycyrrhiza uralensis Fischer or Glycyrrhiza glabra Linne
We found that the GL content per daily dosage in all Kampo extracts are generally proportional to the compounding amount of Glycyrrhizae Radix, except in the case of shoseiryuto

Summary

Introduction

Several investigators have reported that excessive and/or long-term administration of Glycyrrhizae Radix-containing Kampo medicines and crude drug products or GL alone frequently leads to pseudoaldosteronism [13,14,15], such as peripheral edema [16,17,18], hypokalemia [19, 20] and hypertension [21, 22] These adverse effects are thought to result from glycyrrhetinic acid (GA), a major metabolite of GL that inhibits type 2 11b-hydroxysteroid dehydrogenase, leading to an increase in cortisol level instead of cortisone in the kidney. It is still unstated whether the same amount of GL in each Kampo prescription is based on the amount of Glycyrrhizae Radix or not

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