The metabolism and particularly the decarboxylation of methyldopa were studied in hospitalized patients with uncomplicated hypertension. Both unlabeled and radioactive drugs were employed in these studies. Absorption from the intestine, as indicated by plasma levels of the drug and recovery of radioactivity in urine, was shown to be incomplete. The drug disappeared from the plasma with a half-time of less than 2 hours. On the average, about half of the radioactivity administered orally as 2-C¹⁴-methyldopa could be recovered in the urine. That portion not excreted in the urine appeared in the feces. Urinary excretion of radioactivity was rapid and essentially complete within 24 hours.

Confirming previous studies with dl-α-methyl-dopa, the major urinary excretory products of l-α-methyl-dopa (methyldopa, Aldomet) were found to be the drug itself and conjugates thereof. Small fractions appear as other metabolites, the most significant of which is the decarboxylated derivative, αmethyl-dopamine. The pharmacologically inert d-isomer of α-methyl-dopa was found not to be decarboxylated. Alpha-methyl-dopa hydrazine was shown to reduce significantly the excretion of α-methyl-dopamine during treatment with methyldopa but the effects of the latter drug on blood pressure were not altered. On the basis of unchanged urinary excretions of vanilmandelic acid, decarboxylase inhibition during treatment with methyl-dopa was judged to be inadequate to inhibit endogenous synthesis of norepinephrine.

The relationships between metabolism of the drug and clinical response are discussed. The hypothesis is presented and defended that the hypotensive effects of methyldopa are mediated by amine metabolites of the compound, which are formed following its decarboxylation. Probably norepinephrine depletion is the final denominator but other possibilities exist.