Selective rise in brain dopamine by inhibition of extracerebral levodopa decarboxylation

The action of Ro 4‐4602 on decarboxylase of aromatic amino acids (DC) was studied in homogenates of both brain and heart to which the drug had been added and in intact rats after parenteral administration of the compound. Furthermore, investigations on the effect of Ro 4‐4602 on the metabolism of levodopa were carried out in extracerebral tissues as well as in brain of intact rats. In vivo, Ro 4‐4602 preferentially inhibits DC of extracerebral tissues including the brain capillaries. The inhibitor markedly enhances the accumulation of levodopa in the blood. As a consequence, increased amounts of levodopa penetrate through the brain capillaries into the cerebral parenchyma where decarboxylation to dopamine occurs. The newly formed amine is preferentially localized in the extrapyramidal brain centers. Concomitantly, the endogenous 5‐hydroxytryptamine (5‐HT) of the brain decreases. Potential advantages of the combination inhibitor plus levodopa over levodopa alone are: enhanced intestinal absorption of levodopa, decrease of the required levodopa dose, decrease of the peripheral side effects of levodopa, and enhanced selectivity of action of levodopa in the central nervous system.