Impaired distribution of alpha-methyl-L-p-tyrosine in diabetic rats

Although alpha-methyl-L-p-tyrosine (alpha-MPT), an inhibitor of catecholamine synthesis, has been used to study catecholamine turnover in diabetic animals, effects of diabetes on metabolism of the drug have not been investigated. In this study, administration of a standard dose of alpha-MPT (250 mg/kg initially and 125 mg/kg at 2 h intervals) resulted in lower plasma and tissue levels of alpha-MPT and its metabolites in streptozocin-diabetic rats than in controls. Two to six hours after the initial dose 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 and plasma levels of the alpha-MPT metabolite, alpha-methyl DOPA (alpha-MD) were 2-10-fold lower in tissues of diabetic animals. Levels of the alpha-MPT metabolite alpha-methyl norepinephrine (alpha-MNE), measured only in the hypothalamus, were 4-fold lower in diabetic rats than in controls. There were no differences in the ratio of free/conjugated alpha-MPT in plasma. Treatment of diabetic rats with insulin restored alpha-MPT and alpha-MD to control levels. These findings indicate that i.p. administration of alpha-MPT does not result in equivalent levels of the drug in diabetic and control rats and suggest caution in the use of alpha-MPT to compare catecholamine turnover in diabetic and healthy animals.