A possible involvement of 3-monoglucuronyl-glycyrrhetinic acid, a metabolite of glycyrrhizin (GL), in GL-induced pseudoaldosteronism.
Glycyrrhizin (GL), a major ingredient of Glycyrrhiza Radix (licorice), is widely used to treat various disorders or as a sweetener. It is also known that GL occasionally induces pseudoaldosteronism. It is conceivable that the active form of GL in pseudoaldosteronism induction is glycyrrhetinic acid (GA). Although it is reported that 3-monoglucuronyl-glycyrrhetinic acid (3MGA) is detectable specifically in the plasma of patients with GL-induced hypokalemia, pharmacokinetics and a hypokalemia induction mode of action for 3MGA have not been clarified. We investigated the toxicokinetics of GL, GA and 3MGA in a single or multiple oral administration of GL. The results suggested that higher blood concentrations of 3MGA were maintained by the multiple administration compared to the single dose, whereas the concentrations of GA and GL showed no difference. We injected 3MGA intravenously and found that it can decrease the plasma potassium level (PPL) in vivo. It is clinically recommended to avoid a combination treatment of GL and furosemide. While treatment with a low dosage of furosemide had no effect on PPL, the multiple administration of GL and furosemide markedly decreased PPL compared to the effect of administering GL alone. In the single dosage regime, there was no difference between PPL after the combination treatment and after administering GL alone. Collectively, these findings suggested that accumulation of 3MGA may be involved in the pathogenesis of pseudoaldosteronism induced by chronic GL treatment.
Ohtake
Nobuhiro
N
Pharmacology Research Department, Central Research Laboratories, Tsumura & Co., 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki 300-1192, Japan. ootake_nobuhiro@mail.tsumura.co.jp
Kido
Akiko
A
Kubota
Kunitsugu
K
Tsuchiya
Naoko
N
Morita
Toshimi
T
Kase
Yoshio
Y
Takeda
Shuichi
S
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005665:Furosemide / Q000633:toxicity; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D019695:Glycyrrhizic Acid / Q000493:pharmacokinetics / Q000633:toxicity*; D006168:Guinea Pigs; D006929:Hyperaldosteronism / Q000139:chemically induced* / Q000378:metabolism; D007008:Hypokalemia; D007275:Injections, Intravenous; D008297:Male; D011188:Potassium / Q000097:blood; D013549:Sweetening Agents / Q000493:pharmacokinetics / Q000633:toxicity*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D013549:Sweetening Agents; C052400:glycyrrhetyl 3-monoglucuronide; D019695:Glycyrrhizic Acid; D005665:Furosemide; D006034:Glycyrrhetinic Acid; D011188:Potassium