Metabolism of methyldopa in man after oral administration of the pivaloyloxyethyl ester.

In a crossover study, the pivaloyloxyethyl ester (POE) of methyldopa, labeled either with 3H in the methyldopa moiety or 14C in the pivalic acid moiety, was administered orally to four volunteers in 1000-mg single doses (equivalent to 500 mg of methyldopa). The majority (93%) of either the 3H- or 14C-labeled dose was excreted in the urine. Methyldopa, which was assayed by a fluorometric technique, peaked (approximately 6 micrograms/ml) at 1 hr in the plasma. Forty-five per cent of the dose was excreted as methyldopa as opposed to 18% normally seen after oral methyldopa dosages. Intact POE was absent in the urine of three volunteers and present in only trace amounts in urine from a fourth volunteer. Thus, the oral dose of POE was well absorbed and rapidly hydrolyzed to methyldopa. After oral administration of methyldopa, methyldopa sulfate is the principal urinary metabolite in man. However, after administration of POE, a relatively small fraction (13%) of the dose was excreted as methyldopa sulfate. The major urinary metabolite of POE, other than methyldopa, was 3-OCH3 methyldopa. Methyldopamine was a minor metabolite. It was concluded that a shift from sulfation to methylation occurred in the metabolic profile of methyldopa when it was administered as POE and that the metabolites of POE (including conjugated pivalic acid) were rapidly eliminated from the body.