Pharmacological Studies on γ-Guanidinobutyramide

Abstract

γ-Guanidinobutyramide (Tyformin) as the readily soluble hydrochloride (Augmentin; HL 523) has a very low acute toxicity (6 gm/kg p.o. in mice) and chronically it is without observed effect in rats at 250 mg/kg orally over a period of six months. When given orally (800 mg/kg) or subcutaneously (200 mg/kg) to rabbits it depressed blood sugar levels, sometimes sufficiently to produce convulsions. In rats it was active orally (1,400 mg/kg) and subcutaneously (500 mg/kg); any induced convulsions could be stopped by administration of intravenous glucose. Its maximal effect was evident two to four hours after an oral dose. Intravenous doses of 50 mg/kg and above invariably produced hyperglycemia and sometimes death. The compound was active in alloxan-diabetic animals; hypoglycemic doses did not stimulate insulin release in the normal animal.

Glucose uptake by hemi-diaphragm preparations in vitro was stimulated by HL 523 at 1 mg/ml and above as effectively as by insulin, 1 mg of HL 523 being equivalent to 832 µU of insulin. It inhibited conversion of ammonia to urea. This latter action was blocked by methylation of the guanidine group. (HL 523 significantly lowered blood urea levels without elevating urea excretion in the urine.) It is considered that HL 523 has a direct action in increasing peripheral glucose utilization, other than by increasing glycogenesis.

Key words

γ-Guanidinobutyramide - Glycemia - Insulin (Plasma) - Glycogen - Urea

1 Present Address: Guy's Hospital Medical School, London Bridge, S.E. 1

2 Present Address: Glaxo Research Ltd., Greenford, Middlesex, England.