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a-Methyldopa sesquihydrate is used in the treatment of hypertension; over 20 million prescriptions are written annually for a -methyldopa or a-methyldopa sesquihydrate in the United States. a-Methyldopa sesquihydrate (USP grade, greater than 99% pure) was selected for study because of widespread human exposure and the lack of carcinogenicity studies on this compound. Fourteen-day, 13-week, and 2-year studies were conducted in F344/N rats and B6C3F1 mice. The chemical was administered in feed because human exposure is primarily by the oral route. Short-term studies were performed in bacteria and mammalian cells to evaluate the potential for genetic damage. Fourteen-Day and Thirteen-Week Studies: In the 14-day studies, the chemical was administered at dietary concentrations of 0 and 6,250-100,000 ppm. All rats receiving 100,000 ppm and 2/5 female rats receiving 50,000 ppm died. All mice lived until the end of the studies. Final mean body weights of dosed male rats were 14%-43% lower than that of controls, and those of dosed female rats were 9%-24% lower. Feed consumption by dosed male and female rats was reduced. Final mean body weights of dosed mice were generally within 10% of those of controls; feed consumption by dosed groups was lower than that by controls during the first week of the studies. In the 13-week studies, the chemical was administered at dietary concentrations of 0 and 3,100-50,000 ppm. Deaths occurred in 4/10 male rats, 7/10 female rats, and 2/10 female mice at 50,000 ppm and in 1/10 female rats at 25,000 ppm. Final mean body weights of dosed rats were 6%-46% lower than those of controls. Feed consumption by dosed rat groups was lower than that by controls. Final mean body weights of male mice at 25,000 and 50,000 ppm and female mice at 50,000 ppm were reduced 12%-19%. Feed consumption by dosed and control mice was comparable. Rats and mice receiving 25,000 and 50,000 ppm exhibited clinical signs of toxicity including lethargy, hyperexcitability, ocular discharge, and rough hair coats. Clinical signs of toxicity were judged to be more severe in dosed male mice than in female mice. Minimal to moderate kidney tubular cell regeneration was seen in male and female rats at 12,500, 25,000, and 50,000 ppm. Bone marrow hypoplasia occurred in male rats at 25,000 and 50,000 ppm and in female rats at 6,300 ppm and higher. Nuclear enlargement (karyomegaly) of the renal corticaltubular epithelium was observed in male and female mice administered 12,500-50,000 ppm; these kidney lesions were judged to be more severe and occurred more frequently at concentrations of 25,000 ppm and higher. Because of kidney lesions, bone marrow responses, and body weight effects at 12,500 ppm and higher and increased deaths and clinical signs at 25,000 and 50,000 ppm, dietary concentrations selected for male and female rats in the 2-year studies were 0, 3,100, and 6,300 ppm. Based on clinical signs, kidney effects, and body weight decreases at 25,000 and 50,000 ppm, dietary concentrations selected for male and female mice in the 2-year studies were 0, 6,300, and 12,500 ppm. Diets containing the chemical at these concentrations were fed to groups of 50 male and 50 female rats and 50 male and 50 female mice for 103 weeks. Body Weight and Survival in the Two-Year Studies: Mean body weights of dosed rats were generally 8%-17% lower than those of controls, and mean body weights of dosed mice were generally 5%-22% lower than those of controls throughout the studies. The average amount of a-methyldopa sesquihydrate consumed per day was approximately 110-120 or 230-240 mg/kg per day by low and high dose rats and 830-890 or 1,760-1,800 mg/kg by low and high dose mice. Survival was comparable among dosed and control groups (male rats: control, 28/50; low dose, 26/50; high dose, 27/50; female rats: 35/50; 34/50; 29/50; male mice: 44/50; 42/50; 39/50; female mice: 42/50; 40/50; 38/50). Clinical signs considered to be dose-related included fighting in male rats, irritability in male mice, and rough hair coats in female mice. Nonneoplastic and Neoplasle rats, irritability in male mice, and rough hair coats in female mice. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Several lesions of the forestomach, including edema, chronic inflammation, epithelial hyperplasia, and ulcers, were seen at low incidences in high dose rats. No forestomach neoplasms occurred. No neoplastic lesions were observed in either male or female rats which were considered related to a-methyldopa sesquihydrate exposure. Nephropathy (control, 3/50; low dose, 21/50; high dose, 32/50), karyomegaly (nuclear enlargement) of cells of the tubular epithelium (0/50; 46/50; 44/50, and cysts (2/50; 10/50; 10/50) were observed in the kidney of dosed female mice. Low incidences of tubular cell hyperplasia (0/50; 1/50; 1/50), tubular cell adenomas (0/50; 2/50; 0/50), and tubular cell adenocarcinomas (0/50; 0/50; 1/50) were observed in male mice. Tubular cell adenomas (3/2,029, 0.15%) and tubular cell adenocarcinomas (3/2,029, 0.15%)are uncommon in untreated control male B6C3F1 mice. No neoplastic lesions in female mice were considered related to a-methyldopa sesquihydrate exposure. Decreased incidences of several site-specific neoplasms were observed in dosed rats and mice; these decreases might have been due in part to decreased weight gain in dosed groups. The decreases occurred in the adrenal medulla of male rats (pheochromocytomas or malignant pheochromocytomas, combined: 21/49; 3/49; 10/50), uterus of female rats (endometrial stromal polyps: 15/50; 5/49; 1/50), liver of male and female mice (hepatocellular adenomas or carcinomas, combined-- male: 15/50; 5/50; 6/50; female: 4/50; 1/50; 0/50), and anterior pituitary gland of female mice (adenoma: 9/49; 4/40; 2/50). The incidences of malignant tumors (male: 19/50; 9/50; 8/50; female: 21/50; 16/50; 12/50) and benign or malignant tumors (combined) (male: 32/50; 15/50; 17/50; female: 33/50; 22/50; 21/50) were reduced in dosed mice. Reproductive Studies: a-Methyldopa sesquihydrate was administered to male F344/N rats in corn oil by gavage 5 days per week for 65 days at doses of 0, 50, 100, 200, or 400 mg/kg. Decreased body weight was seen in dosed animals. Male rats were mated to untreated female F344/N rats on days 57-61, necropsies were performed on days 65-67, and reproductive toxicity was measured by sperm count, sperm motility, organ weights, hormone levels, and histologic evaluation of the testis. Decreased fertility was observed in males dosed with a-methyldopa sesquihydrate at 200 and 400 mg/kg. Decreases were also seen in sperm count, sperm motility, apparent number of late spermatids, and plasma testosterone levels in males in the 200 and 400 mg/kg groups. This alteration of reproductive function in male rats was found to be reversible after a 13-week recovery period (without dosing). The decreased fertility observed after a-methyldopa sesquihydrate administration was probably due in part to the decreases in plasma testosterone levels. Genetic Toxicity: a-Methyldopa sesquihydrate was not mutagenic when tested with or without exogenous metabolic activation with a preincubation protocol in four strains of Salmonella typhimurium (TA97, TA98, TA100, or TA1535). No increase in chromosomal aberrations or sister chromatid exchanges was observed in Chinese hamsterovary (CHO) cells exposed to a-methyldopa sesquihydrate with or without S9. Audit: The data, documents, and pathology materials from the 2-year studies of a-methyldopa sesquihydrate have been audited. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of a-methyldopa sesquihydrate for male or female F344/N rats fed diets containing 3,100 or 6,300 ppm. There was equivocal evidence of carcinogenic activity of a-methyldopa sesquihydrate for male B6C3F1 mice, as shown by three dosed mice having uncommon tubular cell tumors of the kidney. There was no evidence of carcinogenic activity of a -methyldopa sesquihydrate for female B6C3F1 mice fed diets containing 6,300 or 12,500 ppm. Nonneoplastic lesions of the kidney including karyomegaly were observed in dosed female mice. Decreased incidences of several tumor types (in the adrenal gland in male rats, uterus in female rats, liver in male and female mice, and anterior pituitary gland in female mice) were considered related to a-methyldopa sesquihydrate exposure. Synonyms for a-Methyldopa or a-Methyldopa sesquihydrate: 3-hydroxy-a-methyl-L-tyrosine sesquihydrate; L-(a-MD); a-methyl-L-3,4-dihydroxyphenylalanine; L(-)-b-(3,4-dihydroxyphenyl)-a -methylalanine; L-(-)-3-(3,4-dihydroxyphenyl)-2-methylalanine; L-a-methyl-3,4-dihydroxyphenylalanine; a-methyl-b-(3,4-dihydroxyphenyl)-L-alanine; L-(-)-a-methyl-b-(3,4-dihydroxyphenyl)alanine; (-)-methyldopa; L-methyldopa; L-a-methyldopa; a-methyl-L-dopa Trade Names for a-Methyldopa or a-Methyldopa sesquihydrate: Aldomet; Aldometil; Aldomin; a-Medopa; AMD; Bayer 1440 L; Baypresol; Dopamet; Dopatec; Dopegyt; Hyperpax; Medomet; Medopren; Methoplain; MK. B51; MK-351; Presinol; Presolisin; Sedometil; Sembrina
A retrospective analysis of previous studies examining methyldopa absorption suggested the possibility that the absorption of methyldopa might increase on repeat methyldopa ingestion. A prospective study was undertaken to determine the effect of repeated oral doses of methyldopa on methyldopa absorption. Thirteen healthy subjects ingested single 250 mg methyldopa doses on days 0, 7, 14, 28, 56, and 112; 24 urine samples were collected and analyzed for methyldopa and its major metabolites on each study day and methyldopa plasma levels were measured over 8 hours at days 0 and 56. There were significant increases in the absorption of methyldopa (as estimated by the urinary excretion of methyldopa and the measured metabolites over 24 hours) at day 56 (33.4 +/- 8.9%, P less than .025) compared with day 0 (26.0 +/- 10.8%). There was also a significant increase in renal clearance of unmetabolized methyldopa (62.7 +/- 13.6 vs. 99.3 +/- 29.1 mL/min, P less than .01) and a decrease in the plasma half-life of methyldopa at day 56 (2.22 +/- 0.91 vs. 1.56 +/- 0.68 hr, P less than .05). There was a tendency toward increases in methyldopa absorption at day 7, 14, 28, and 112. Several possible explanations for the changes in methyldopa disposition are discussed.
Sulfate conjugation catalyzed by phenol sulfotransferase (PST) is the major metabolic pathway for methyldopa. Methyldopa is also O-methylated in a reaction catalyzed by catechol-O-methyltransferase (COMT). Our studies were performed to determine whether sodium sulfate alters methyldopa metabolism. Methyldopa powder, 3.5 mg/kg, was taken with and without sodium sulfate, 13.25 mg/kg, by 24 subjects in a randomized, crossover design. Compared with results obtained when only methyldopa was taken, sodium sulfate taken with methyldopa increased the proportion of drug excreted as methyldopa sulfate expressed as the percentage of all urinary metabolites (66.0% +/- 5.3% and 50.1% +/- 7.5%; means +/- SD). The percentage of free methyldopa excreted also decreased (17.1% +/- 3.7% and 27.3% +/- 5.5%). Platelet PST and red blood cell COMT activities were measured in blood samples from these subjects. When sodium sulfate was taken with methyldopa, there was a significant correlation between platelet PST activities and percentages of metabolites excreted as methyldopa sulfate (r = 0.545; P less than 0.01). This correlation was not significant when methyldopa was taken alone (r = -0.340; P greater than 0.10). There was a significant correlation between red blood cell COMT activities and the proportion of urinary metabolites excreted as 3-O-methyl-alpha-methyldopa when methyldopa was taken alone (r = 0.532; P less than 0.01) but not when it was taken with sodium sulfate (r = 0.153; P greater than 0.20). Our data support the conclusion that variation in sulfate availability may be one factor responsible for individual differences in the metabolism of clinically used doses of methyldopa.(ABSTRACT TRUNCATED AT 250 WORDS)
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.
The effect of the cardioselective beta-adrenoreceptor blocking compound, metoprolol, was compared with methyldopa in the long-term management of hypertension. Thirty patients given metoprolol and twenty-six given methyldopa were treated for 2 years. The maximum dose of metoprolol was 200 mg twice daily (average 308 mg) and of methyldopa 1,000 mg twice daily (average 1,120 mg). Blood pressure was similar at entry to the study (metoprolol 177/110 mmHg and methyldopa 181/111 mmHg). After 2 years of treatment the blood pressure levels were again similar (metoprolol 149/91 mmHg and methyldopa 148/91 mmHg). Erect pressures were lower in the methyldopa group, but there was no difference between supine and erect blood pressure levels in those on metoprolol. At an exercise load of 300 and 600 kpm the increase in systolic pressure was significantly less in the metoprolol group. The proportional increase in systolic and diastolic pressure in response to a standardized stress situation was reduced by treatment with metroprolol but not by methyldopa. Tolerance to therapy did not develop in either group. The main difference between metoprolol and methyldopa was in the incidence and severity of side effects. Four patients were withdrawn from the metoprolol group. Seventeen were withdrawn from the methyldopa mainly because of side effects including drowsiness, depression, skin rash, and impotence. Six patients on metoprolol and seventeen on methyldopa continued on therapy although side effects were present. It is concluded that metoprolol and methyldopa lower blood pressure to the same extent, but metoprolol is advantageous because of a lower incidence of side effects.
Methyldopa therapy for hypertension after renal transplantation could affect graft outcome adversely, since methyldopa inhibits suppressor cells. To study effects of methyldopa on transplant outcome, we analyzed prospective data on 1,648 hypertensive, first-allograft recipients; 545 patients used methyldopa and 1,103 patients did not. One-year graft functional survival was 66% and 67% for all patients using and not using methyldopa respectively. No increased acute rejection occurred related to methyldopa. During the one to six years of follow-up, no adverse effects on graft survival could be attributed solely to methyldopa except that graft survival among white recipients using methyldopa was diminished late after transplantation (P less than .05). Patient survival was not affected by methyldopa. Azathioprine and prednisone therapy may avert the suppressor cell inhibition by methyldopa. Its effect on kidney transplant outcome is not significant except in whites late in the course of graft function; methyldopa use when clinically indicated appears safe.
The possible role of the endogenous opioid system in the central hypotensive mechanism of action of alpha-methyldopa was investigated. Conscious normotensive Wistar rats were used in this study and all treatments were given intracisternally. Pretreatment with the opiate receptor antagonist naltrexone resulted in a parallel shift to the right of the dose-response curve for alpha-methyldopa, both for blood pressure and heart rate. In addition, when increasing doses of naltrexone and a constant dose of alpha-methyldopa were used the opiate receptor antagonist inhibited dose-dependently alpha-methyldopa-induced hypotension but not the bradycardia. Administration of naltrexone after the injection of alpha-methyldopa failed to reverse or inhibit alpha-methyldopa-induced hypotension, indicating that the interaction between alpha-methyldopa and the endogenous opioid system occurs at the start of the action of alpha-methyldopa. An antiserum against endorphins also inhibited the fall in blood pressure after alpha-methyldopa. These findings indicate that stimulation of opiate receptors, probably by an endorphin, is involved in the mechanism of action of alpha-methyldopa and that this stimulation seems to occur at the start of the action of alpha-methyldopa.
This study examined the effect of two widely used iron treatments on methyldopa absorption, metabolism, and blood pressure control. A 500 mg tablet of methyldopa (2.37 mmol) was taken with and without ferrous sulfate (325 mg) by 12 normal subjects in a randomized crossover trial. When ferrous sulfate was taken with methyldopa there was a decrease in the proportion of methyldopa excreted as "free" methyldopa (49.5% +/- 12.4% vs 21.1% +/- 4.77%; p less than 0.01), a significant increase in the proportion excreted as methyldopa sulfate (37.8% +/- 12.3% vs 65.8% +/- 10.5%; p less than 0.01), and a decrease in the percentage of methyldopa absorbed (29.1% +/- 12.5% vs 7.88% +/- 4.14%; p less than 0.01). These factors resulted in an 88% reduction in the quantity of "free" methyldopa excreted. To determine if an iron preparation without sulfate produced the same effect, the study was repeated with ferrous gluconate (600 mg) with similar results. The clinical consequences of the methyldopa-ferrous sulfate interaction was determined in five hypertensive subjects receiving chronic methyldopa therapy. The subjects took ferrous sulfate for 2 weeks. There was an increase in both systolic and diastolic blood pressure in four patients and a decrease in blood pressure in all patients after ferrous sulfate was discontinued. The increases in blood pressure were substantial in three of the patients.
Kirtland et al (1980) suggested that methyldopa caused the production of red cell (RBC) autoantibodies by causing a persistent increase in lymphocyte cyclic AMP, which inhibited suppressor T cell function, leading to unregulated autoantibody production in some patients. They showed that significantly higher lymphocyte cyclic AMP concentrations were generated by lymphocytes from healthy donors after adding methyldopa, and by lymphocytes from patients who were receiving methyldopa compared to lymphocytes from healthy donors without methyldopa present. They also showed that methyldopa affected suppressor cell activity. We measured the effect of methyldopa and procainamide on suppressor cell activity, using a similar approach to Kirtland et al (1980). Suppressor cell activity was measured by measuring the amount of IgG, produced in vitro, by B cells following mitogen stimulation preceded by a 24 h incubation period. We found no significant increase in the amount of IgG generated by normal donor lymphocytes, when methyldopa or procainamide was present during the preincubation period. This is in contrast to the findings of Kirtland et al (1980). We also measured the amount of IgG generated in vitro by mitogen-stimulated lymphocytes from patients (with and without positive direct antiglobulin tests) taking methyldopa and compared this to the amount of IgG generated by lymphocytes from normal donors and patients (with and without positive direct antiglobulin tests). The results were similar for each group. This does not agree with the findings of Kirtland et al (1980) who found that lymphocytes from patients taking methyldopa produced more IgG in vitro than lymphocytes from normal donors. Our results do not support the hypothesis that methyldopa and procainamide induce autoantibodies by affecting suppressor cell function.
1. This study served to investigate whether endogenous opioid peptides play a role in the putative antinociceptive and the sedative actions of alpha-methyldopa. 2. In conscious normotensive rats, alpha-methyldopa induced hypotension, starting around 1 h and reaching a maximum 3-4 h after administration. Pretreatment with naltrexone resulted in an inhibition of alpha-methyldopa-induced hypotension. 3. alpha-Methyldopa dose-dependently increased hot plate latency which became evident after a 4 h lag period and reaching a maximum effect at 6 h. The antinociceptive effect of alpha-methyldopa was not affected by naltrexone. 4. In a small open field, alpha-methyldopa dose-dependently suppressed locomotion and sniffing behaviour. These effects of alpha-methyldopa were apparent 1 h after administration and were naltrexone-insensitive. 5. No changes in the level of beta-endorphin-like immunoreactivity in plasma and cerebrospinal fluid were observed after administration of alpha-methyldopa. 6. The results indicate that endogenous opioid peptides are involved in the hypotensive action of alpha-methyldopa but not in alpha-methyldopa-induced hypomotility and antinociception.
The present study was performed to gain more information on the nature of the opioid peptide(s) involved in the mechanism of action of alpha-methyldopa. Conscious, normotensive Wistar rats were used and all treatments were given intracisternally. For blood pressure and heart rate, pretreatment with a midportion beta-endorphin antiserum resulted in a parallel shift to the right of the dose-response curve for alpha-methyldopa. In addition, when rats were pretreated with various dilutions of this antiserum and treated with a constant dose of alpha-methyldopa, the antiserum dose-dependently inhibited alpha-methyldopa-induced hypotension and bradycardia. Using antisera specifically recognizing the C-terminus of beta-, gamma- and alpha-endorphin, respectively, revealed that only the beta-endorphin antiserum inhibited the decrease in blood pressure seen after administration of alpha-methyldopa. An antiserum against [Met5]enkephalin did not influence the cardiovascular responses following alpha-methyldopa. On the other hand, a dynorphin(1-13) antiserum also inhibited in a dose-dependent manner the hypotension induced by alpha-methyldopa. When administered 3 h after the injection of alpha-methyldopa, the beta-endorphin and dynorphin(1-13) antisera failed to reverse the hypotension induced by alpha-methyldopa. The results favor a role for beta-endorphin(1-31) and dynorphin(1-13) in the hypotension centrally mediated by alpha-methyldopa.
To assess the problem of alpha-methyldopa dosing in lactating mothers with hypertension, we studied three breast-feeding women to determine simultaneous plasma and breast milk concentrations of alpha-methyldopa after a 500 mg oral dose while receiving continuous therapy. Peak excretion of free alpha-methyldopa in breast milk ranged from 0.02 to 1.14 microgram/ml. The breast milk/whole plasma ratios of alpha-methyldopa ranged from 0.19 to 0.34. In two of the three breast-fed infants, plasma levels of alpha-methyldopa were undetectable (less than 0.05 microgram/ml) 6 hours after maternal ingestion of the drug, but in one of these the plasma alpha-methyldopa concentration was 0.09 microgram/ml 10 hours after maternal dosing. It is estimated that when the mother receives 1 gm alpha-methyldopa a day, the maximal cumulative dose of alpha-methyldopa would be 855 micrograms and the average cumulative alpha-methyldopa load to the breast-fed infant would be 195 micrograms, or 0.02% of the maternal dose.
1. alpha-Methyldopa (300 mg/kg i.p.) produced a fall in blood pressure in conscious genetic hypertensive rats. Pretreatment with intraventricular 6-hydroxydopamine prevented this hypotensive effect of alpha-methyldopa, whilst intravenous 6-hydroxydopamine reduced but did not prevent the hypotension.2. The hypotensive effect of alpha-methyldopa was prevented or reversed by intraventricular injection of phentolamine (200 mug/rat).3. Pressor responses obtained by stimulation of the entire sympathetic outflow in the Gillespie & Muir preparation, were unaffected by pretreatment with alpha-methyldopa (300 mg/kg i.p.).4. Vasoconstrictor responses to periarterial nerve stimulation of the isolated renal artery preparation of the rat were markedly reduced by pretreatment with alpha-methyldopa. Furthermore, alpha-methylnoradrenaline was found to have one-eighth the vasoconstrictor potency of noradrenaline in this particular artery preparation.5. Pressor responses obtained by stimulation of the posterior hypothalamus or midbrain reticular formation in the rat anaesthetized with urethane were markedly reduced by pretreatment with alpha-methyldopa. FLA-63, a selective dopamine-beta-hydroxylase inhibitor, prevented the reduction of the pressor responses to hypothalamic stimulation produced by alpha-methyldopa.6. Stimulation of the posterior hypothalamus in the anaesthetized cat caused both an increase in sympathetic nerve activity and a rise in blood pressure. These responses were markedly reduced 3-4 h after the injection of alpha-methyldopa (100 mg/kg i.v.).7. These results strongly suggest that the central actions of alpha-methyldopa are important for its hypotensive effect, although a possible peripheral effect cannot be excluded.