薬理と治療

Abstract

Monoammonium glycyrrhizinate（MGL）has been used for patients with chronic hepatitisin Japan. Chronic toxicity of MGL was examined in CD rats by subcutaneous administrationat the doses of 25, 75 and 225 mg／kg for main study, and of 225 mg／kg for recovery study. Inthe main study, mortality occurred at 225 mg／kg. Increase of swelling, eschar formation andinflammation with hemorrhage, brown pigment and granulation tissue／fibrosis at the injectionsites were recorded dose−dependently at more than 75 mg／kg. Increase of serum bilirubinand decrease of serum chloride and potassium were found at 75 or 225 mg／kg. Decrease oferythrocyres and increase of reticulocytes, neutrophiles and monocytes were observed in 225mg／kg. The relative and absolute kidney weights were increased dose−dependently withswollen and degenerated tubuli contorti with brownish pigment. The increased relative andabsolute liver weights with hypertrophy of the hepatocytes were found at 75 or 225 mg／kg.The toxicokinetic evaluation exhibited a dose related increase in Cmax and AUC for glycyrrhizinand glycyrrhetic acid with no signs of an accumulation with time. At the end of recoveryperiod, brown pigment and granulation tissue／fibrosis at the injection sites, increased kidneyweights with swollen and degenerated tubuli contorti, and increased liver weights werestill remained. However, all other findings observed in treatment period were subsided ornormalized. It clearly indicated a reversibility of the changes derived from MGL administration.The no−observed−adverse−effect level（NOAEL）by subcutaneous administration ofMGL was 25 mg／kg／day. The difference between the NOAEL and appropriate clinical dosesupports enough clearance for safety margin of MGL.（Jpn Pharmacol Ther 2008；36：1025−37）KEY WORDS Glycyrrhizin, Chronic toxicity, Subcutaneous administration, Rat