Effect of carbidopa (MK-486) on the metabolic fate of L-3,4-dihydroxyphenylalanine (L-dopa). I. Effect of carbidopa on the tissue dopa decarboxylase and on the L-dopa-2-14C uptake by the brain in rats.

Abstract

The inhibitory effect of Carbidopa (MK-486) on L-3, 4-dihydroxyphenylalanine (DOPA) decarboxylase in various tissues including the brain was investigated as well as the distribution of Carbidopa-14C in rats. The increase in the brain uptake of radioactive L-DOPA by Carbidopa was demonstrated. Carbidopa, highly distributed in the kindney, lung, and liver, strongly inhibited DOPA decarboxylase activity in the main tissue except the brain in a dose dependent fashion. In spite of a rapid elimination of Carbidopa itself, the inhibitory effect appeared to retain for a long period, i.e., more than 24 hr. With a high dose of Carbidopa, the activity in the brain appeared to be inhibited appreciably. It was proved, however, that this was due to the drug contained in the cerebral blood by the determination of decarboxylase activity or radioactive Carbidopa in the brain perfused with saline, confirming that Carbidopa is a peripheral inhibitor. Carbidopa-14C was found to be distributed highly in the aorta walls which was presumed to be due to a non-specific binding to elastine in the tissue. Carbidopa enhanced the brain uptake of radioactive L-DOPA linearly to the dose of L-DOPA. The effect depended upon the proportion of oral Carbidopa to L-DOPA, and the mixing ratio around 1 : 10 was suggested to be the most efficient combination to elevate the brain uptake of L-DOPA.