Combined Clinical and Metabolic Study of the Effects of Alpha-Methyldopa on Hypertensive Patients
The urinary metabolites of orally administered 2-14C-labeled α-methyldopa were measured in 20 hypertensive patients before and after treatment with α-methyldopa in a dose of 3.0 g daily for 3 months. There was considerable variation in the absorption, biotransformation and excretion of α-methyldopa after an oral dose, but differences in clinical response to α-methyldopa could not be attributed to this.
Approximately 40% of the urinary excretion products of α-methyldopa was recovered as unchanged methyldopa, 31% as α-methyldopa-O-sulfate, 8% as 3-methoxy-α-methyldopa, 9% as neutral fraction, 3% as free base, and 3% as conjugated base.
The percentage of 3-methoxy-α-methyldopa was increased following prolonged treatment with α-methyldopa, suggesting induction of catechol-O-methyl transferase. The percentage of 3-methoxy-α-methyldopa at the final study was correlated with reductions in standing blood pressure, but not with supine blood pressure. No other changes in the metabolism of α-methyldopa could be attributed to chronic administration of the drug, and no correlation was found between the excretion patterns of the other urinary metabolites of α-methyldopa and hypotensive effect. Tolerance to the hypotensive effect of α-methyldopa occurred in four patients, but in another four an increasing hypotensive effect was seen. The development of tolerance to the hypotensive action of α-methyldopa could not be explained on a metabolic basis.
The inhibition of decarboxylation of tyrosine to tyramine and of tryptophan to tryptamine was studied at the initiation of therapy and again after chronic treatment with α-methyldopa. In the majority of patients, inhibition of decarboxylase was markedly increased after chronic treatment, especially when tryptophan was the substrate. In four patients, tolerance to the inhibition of decarboxylation of tyrosine, but not of tryptophan, occurred, and in three of these patients a good hypotensive effect was maintained. There was no correlation between the inhibition of decarboxylase and reduction of blood pressure.
- © 1966 American Heart Association, Inc.