This study examined the pharmacokinetics and metabolism of methyldopa after giving single 250-mg oral and intravenous doses to 16 healthy human volunteers. A 48-hour washout period was allowed between oral and intravenous treatments. Blood and urine samples were collected; methyldopa was assayed in blood and urine, and its metabolites (methyldopa sulfate, alpha-methyldopamine, and alpha-methyldopamine sulfate) were assayed in urine. Pharmacokinetic parameters were recorded as follows: half-life was 2.0 +/- 0.7 hours; total body and renal clearance were 268 +/- 72 and 107 +/- 35 mL/min, respectively; and volume of distribution at steady-state was 33 +/- 11 L. The absolute bioavailability of the drug was 42 +/- 16%. The measurable metabolites in urine after oral and intravenous administration accounted for 27% and 17% of the dose, respectively. Methyldopa sulfate was the most abundant metabolite recorded; its quantity was higher after oral than after intravenous administration, 20.1 +/- 5.7% versus 6.7 +/- 5.3% of the dose (P < .05), suggesting significant presystemic gut metabolism. First-pass gut metabolism for methyldopa was estimated to be 17.6 +/- 6.9% of the dose given.