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At least 19 recordsLinked to original sources
PubMed1975

Plasma concentration of alpha-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.

Administration, Oral↗
PubMed1982

Pharmacokinetics of the pivaloyloxyethyl (POE) ester of methyldopa, a new prodrug of methyldopa.

A prodrug of methyldopa, the pivaloyloxyethyl (POE) ester, was administered orally to healthy human volunteers at doses equivalent to 500 and 1000 mg of methyldopa and was compared to oral and intravenous doses of methyldopa. The time courses of availability of methyldopa to the general circulation were compared and contrasted with the model-independent estimates of total systemic availability. The POE ester of methyldopa is completely hydrolyzed on the first pass; delivery of methyldopa to the general circulation was faster, more uniform, and more extensive compared to orally administered methyldopa. The systemic availability of methyldopa averaged 64% of the dose with a coefficient of variation (CV) of 15% for the prodrug treatments compared to 27% of the dose with a CV of 63% for methyldopa. First-pass metabolism of drug to the mono-O-sulfate conjugate of methyldopa was lower for the POE ester than for methyldopa.

Absorption↗
PubMed1990

Ferrous sulfate reduces methyldopa absorption: methyldopa: iron complex formation as a likely mechanism.

Ferrous sulfate and sodium sulfate reduce methyldopa absorption in humans. This current study was conducted to investigate some of the potential factors by which these compounds could reduce methyldopa absorption. A rat model developed to examine drug absorption was used. Solutions of 14C methyldopa alone and with ferrous sulfate or sodium sulfate were injected in vivo into closed duodenal segments. Ferrous sulfate reduced methyldopa absorption 52.9% (p less than 0.01), while sodium sulfate had no significant effect on methyldopa absorption. In vitro iron in its ferrous form rapidly oxidizes to the ferric form in the presence of methyldopa. The ferric form of iron binds strongly to methyldopa, presumably resulting in the decreased methyldopa absorption. Methyldopa was stable in vivo and in vitro in the presence of ferrous sulfate and sodium sulfate. These studies are consistent with ferrous sulfate reducing methyldopa absorption by the formation of ferric iron: methyldopa complexes.

Animals↗
PubMed1995

Methyldopa kinetics before and after ingestion of methyldopa for eight weeks.

Methyldopa urine and plasma levels and urine metabolite levels were assessed following intravenous (IV) and oral (PO) methyldopa before, and after ingestion of methyldopa (500 mg) daily for eight weeks. There was no increase in (estimated) methyldopa absorption (8.4%) or renal clearance (PO 13.9%, IV 2.33%) after the eight weeks of methyldopa ingestion. However, the initial methyldopa absorption and renal clearance values in this study were higher than that in previous studies. There was an inverse relation between the initial methyldopa absorption and the change in absorption (r - 0.605) and between the initial methyldopa renal clearance and the change in renal clearance (PO r -0.874, IV r -0.891). Overall, this study did not confirm our previous studies showing induction of methyldopa absorption and renal clearance, possibly due to prior up regulation of transporter function. Consistent with methyldopa inducing drug transporters, those with low initial absorption and renal clearance values had the greatest increases.

Absorption↗
PubMed1983

Liquid chromatographic determination of methyldopa and methyldopa-thiazide combinations in dosage forms.

A liquid chromatographic (LC) method, using a reverse phase C18 column, an acetic acid-methanol-water mobile phase, and detection at 280 nm, was developed for the determination of methyldopa in tablets and oral suspensions and combinations of methyldopa with hydrochlorothiazide or chlorothiazide in tablets. A mixture of these 3 drugs was resolved in less than 8 min. Detector responses were linear for the following amounts (mg/mL) of drug injected: methyldopa 0.031-0.393, chlorothiazide 0.019-0.114, and hydrochlorothiazide 0.004-0.083. Recoveries from commercial dosage forms ranged from 99.1 to 100.9% for methyldopa, 99.2-100.4% for chlorothiazide, and 100.0-101.2% for hydrochlorothiazide. Replicate injections of methyldopa, chlorothiazide, and hydrochlorothiazide standard preparations alone or in combination gave overall relative standard deviations of less than 1.6% (n = 10). The results for methyldopa tablets by the proposed method were in agreement with those obtained by the USP XX method. The LC method detected as little as 0.6 micrograms 3-O-methylmethyldopa/mL and 0.5 micrograms 4-amino-6-chloro-1,3-benzenedisulfonamide/mL, which are sometimes found as contaminants of methyldopa and thiazides, respectively, and resolved methyldopa from its methyldopa glucose adduct, a substance found in methyldopa oral suspensions.

Chlorothiazide↗
PubMed1978

The combined use of L-alpha-methyldopa hydrazine and methyldopa in the treatment of hypertension.

1. The combined use of alpha-methyldopa and L-alpha-methyldopa hydrazine (a peripheral decarboxylase inhibitor) has been studied, in a double-blind cross-over comparison, with alpha-methyldopa and L-alpha-methyldopa hydrazine placebo in the treatment of eight patients with essential hypertension. 2. L-alpha-methyldopa hydrazine did not enhance the antihypertensive effect of alpha-methyldopa. This suggests that because methyldopa can inhibit its own decarboxylation, peripheral decarboxylation is not an important metabolic pathway for methyldopa and elevated brain levels of methyldopa do not necessarily result in elevated brain levels of methyldopamine.

Adult↗
PubMed1981

Long-term treatment of hypertension with methyldopa. IV. Duration of methyldopa therapy.

Methyldopa was administered for an average of 3 years to 435 patients with essential hypertension who were included in this retrospective survey. In 73% of patients, methyldopa was added to prior diuretic therapy, and in 19%, methyldopa and a diuretic were started concurrently. The remaining patients (8%) started treatment with methyldopa alone. After the initiation of methyldopa administration, a diuretic and/or additional antihypertensive agent(s) was included in the treatment regimen of 167 (38%) of the 435 patients. Treatment was interrupted in 147 patients - 14 (3%) because of lack of response, 73 (17%) with adverse effects, and 60 (14%) because of other or unknown reasons. Two-thirds of the patients treated had been receiving methyldopa continuously up to the time these data were collected in early 1979.

Adolescent↗
PubMed1990

Pineal gland as a model to elucidate the primary mode of action of alpha-methyldopa: alpha-methyldopa induces an increase in the synthesis of N-acetylserotonin and melatonin levels by the rat pineal gland.

An attempt was made to use the pineal gland as a model for the study of the primary mode of action of alpha-methyldopa, which is still unclear. Organ cultures of pineal glands from rats treated chronically with alpha-methyldopa showed enhanced conversion of radio-active serotonin to melatonin (aMT) as well as its precursor, N-acetyl-serotonin (aHT). This treatment was also found to raise serotonin-N-acetyltransferase (NAT) activity. These increases associated with alpha-methyldopa treatment were further enhanced by the beta-adrenergic agonist, isoproterenol, suggesting a supersensitivity-type effect occurring at the level of the beta-receptor. A subsequent binding study, however, showed a decrease in beta-receptor binding with exposure to alpha-methyldopa, providing mitigating evidence against the occurrence of a supersensitivity phenomenon. It is possible that a metabolite of alpha-methyldopa acts as an alpha 1 and beta-agonist, resulting in greater melatonin (aMT) and N-acetylserotonin (aHT) synthesis than by a beta-agonist, isoproterenol.

Animals↗
PubMed1989

Use of the peptide carrier system to improve the intestinal absorption of L-alpha-methyldopa: carrier kinetics, intestinal permeabilities, and in vitro hydrolysis of dipeptidyl derivatives of L-alpha-methyldopa.

Intestinal permeabilities of five dipeptidyl derivatives of L-alpha-methyldopa (I) were studied by an in situ intestinal perfusion method. The dipeptides displayed a significant increase in their permeabilities compared to L-alpha-methyldopa. The increases ranged from 4 to 20 times. These results suggest that the peptide transport system is less structurally specific than the amino acid transport systems and can be used as an absorption pathway for peptide analogues. The kinetic advantage demonstrated by the dipeptide, L-alpha-methyldopa-L-phenylalanine, over the amino acid analogue, L-alpha-methyldopa, suggests that the peptide carrier would be a possible route for improving the intestinal absorption of pharmacologically active amino acid analogues. Furthermore, the preliminary results of in vitro hydrolysis studies of selected dipeptidyl derivatives indicate that the peptide carrier system could be used as a base for a prodrug strategy.

Animals↗
PubMedDate not supplied

Liquid chromatographic determination of methyldopa and methyldopa-thiazide combinations in tablets: collaborative study.

A reverse phase liquid chromatographic method for the determination of methyldopa, methyldopa-hydrochlorothiazide, and methyldopachlorothiazide in tablets was collaboratively studied by 8 laboratories. Each collaborator received 20 samples that included drug substance, synthetic and commercial tablet compositions. The overall repeatability and reproducibility standard deviations for commercial tablets were 1.11 and 1.75% for methyldopa, 0.96 and 1.62% for chlorothiazide, and 1.21 and 2.15% for hydrochlorothiazide, respectively. The overall recoveries of methyldopa, chlorothiazide, and hydrochlorothiazide added to synthetic tablets were 100.78, 100.70, and 101.34%, respectively. The method has been adopted official first action.

Chlorothiazide↗
PubMed1980

Antihypertensive efficacy of alpha-methyldopa, chlorothiazide and Supres-150 (alpha-methyldopa-chlorothiazide).

Twenty-two white men and two white women with uncomplicated essential hypertension participated in a randomized double-blind trial comparing placebo with alpha-methyldopa (750 mg/d orally) and chlorothiazide (450 mg/d orally), alone or in combination. There were no significant differences in blood pressures as measured with the patients lying down; however, with the patients standing the systolic, diastolic and mean arterial blood pressures were significantly lower (P < 0.05) after treatment with alpha-methyldopa or the combination product. The higher the blood pressure before treatment, the greater the fall with treatment. Adverse effects were infrequent.

Adult↗
PubMed1978

Alpha-methyldopa and drug fever. A study of the metabolism of alpha-methyldopa in patients and normal subjects.

The metabolism of alpha-methyldopa was studied in 5 patients with febrile reactions to the drug, and compared with the metabolism in 5 patients without such reactions and in 4 normal subjects. A depression of the drug metabolism was found in drug fever patients, which may affect either the intestinal mucosal conjugation of the drug or the hepatic transformation. The decreased metabolism is assumed to be a possible causative mechanism of the adverse reaction.

Adult↗