Plasma concentration of ?-methyldopa and sulphate conjugate after oral administration of methyldopa and intravenous administration of methyldopa and methyldopa hydrochloride ethyl ester

The plasma concentrations of free alpha-methyldopa and methyldopa sulphate conjugate were measured in 7 hypertensive patients with normal renal function following alpha-methyldopa (1 g) orally. Five of these patients subsequently received alpha-methyldopa ethyl ester (250 mg) (methyldopate) intravenously and two further patients received 250 mg of alpha-methyldopa intravenously. After oral administration a large amount of total plasma alpha-methyldopa was present as sulphate conjugate. There were wide interindividual differences in the ratio of free: conjugated alpha-methyldopa in plasma (ratio at 4 hours ranged from 3.73-0.83) suggesting that individual differences in the extent of sulphate conjugation may occur. There was no close correlation between the degree of conjugation and the fall in arterial pressure. At all time intervals examined, plasma concentrations were higher following intravenous alpha-methyldopa than alpha-methyldopate. The plasma concentration of alpha-methyldopa (free and esterified) 60 minutes after i.v. alpha-methyldopate was 1.7+/-0.3 mug/ml while at the same time after the same dose of methyldopa by the same route the mean concentration was 5.9 mug/ml. Although small amounts of sulphate conjugate were detected after i.v. alpha-methyldopate, insignificant quantities of conjugate were found after i.v. alpha-methyldopa. The average fall in mean arterial pressure was 27 mm/Hg following i.v. alpha-methyldopa but only 2.7 mm Hg following alpha-methyldopate. These results suggest that sulphate conjugation of alpha-methyldopa occurs in the gastrointestinal tract during absorption. Hydrolysis of alpha-methyldopa ethyl ester does not appear to be instantaneous and pharmacokinetic differences between the ester and free alpha-methyldopa have been demonstrated.