THE METABOLISM OF METHYLDOPA IN HYPERTENSIVE HUMAN SUBJECTS

¹ Merck Sharp & Dohme Research Laboratories, Division of Merck & Co., Inc., Rahway, New Jersey
² The Hypertension Nephritis Clinic of Presbyterian Hospital, New York, N. Y.

Methyldopa labeled with C¹⁴ was administered orally to 20 patients with hypertensive cardiovascular disease together with unlabeled methyldopa at antihypertensively effective doses. The metabolic fate of approximately 90% of the drug was accounted for utilizing chromatographic fractionation techniques.

About one-half of an oral dose was absorbed; peak plasma levels occurred in 3 to 6 hours. Eighty to ninety per cent of the drug was eliminated from the body in 48 hours if renal function was normal. Delayed urinary excretion and prolonged plasma levels occurred with azotemia. A significant fraction (30%) of the drug was present in plasma as methyldopa mono-O-sulfate. Methyldopa was excreted unchanged in the stool.

The major urinary excretion products were: methyldopa (avg. 24%), methyldopa mono-O-sulfate (avg. 64%), 3-O-methyl methyldopa (avg. 4%), a neutral fraction (avg. 3.5%) containing a sulfate conjugate of a neutral metabolite of unknown structure, and a base fraction (avg. 3-10%) containing unconjugated and conjugated excretion products, the largest single constituent of which was the decarboxylation product. -methyldopamine.

VMA excretion was not appreciably changed as a result of methyldopa therapy.

-Methyldopamine in oral doses from 3 to 300 mg did not change the blood pressure of two hypertensive patients. Given intramuscularly (in 25- to 50-mg doses), it also failed to lower blood pressures of another three hypertensive patients who subsequently responded to methyldopa, even though the amounts of -methyldopamine recovered in the urine after injection exceeded those appearing in the urine when the patients were treated with methyldopa.