IMPAIRED DISTRIBUTION OF ALPHA-METHYL-L-P-TYROSINE IN DIABETIC

Although alpha-methyl-L-p-tyrosine (alpha-MPT), an inhibitor of catech olamine synthesis, has been used to study catecholamine turnover in di abetic animals, effects of diabetes on metabolism of the drug have not been investigated. In this study, administration of a standard dose o f alpha-MPT (250 mg/kg initially and 125 mg/kg at 2 h intervals) resul ted in lower plasma and tissue levels of alpha-MPT and its metabolites in streptozocin-diabetic rats than in controls. Two to six hours afte r the initial close of alpha-MPT, concentrations of alpha-MPT were 2-8 -fold lower in the hypothalamus, medulla/pons, and plasma of diabetic animals than in controls, Brain add plasma levels of the alpha-MPT met abolite, alpha-methyl DOPA (alpha-MD) were 2-10-fold lower in tissues of diabetic animals. Levels of the alpha-MPT metabolite alpha-methyl n orepinephrine (alpha-MNE), measured only in the hypothalamus, were 4-f old lower in diabetic rats than in controls, There were no differences in the ratio of free/conjugated alpha-MPT in plasma. Treatment of dia betic rats with insulin restored alpha-MPT and alpha-MD to control lev els. These findings indicate that i.p. administration of alpha-MPT doe s not result in equivalent levels of the drug in diabetic and control rats and suggest caution in the use of alpha-MPT to compete catecholam ine turnover in diabetic and healthy animals.