Pharmacokinetics of methyldopa in healthy man

Stenbaek, O; Myhre, E; Rugstad, Hans Erik; Arnold, Elisabeth; Hansen, Tonya Moen

doi:10.1007/bf00645132

Cited by 26 publications

(8 citation statements)

References 11 publications

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“…The peak effect is delayed and occurs 6-9 h after the dose; the effect then declines with a half-life of approximately 10 h and only a small effect remains by 24-26 h. This time course is similar (0) to that found in earlier studies where the antihypertensive effect was measured after a single oral dose (Dollery & Harrington, 1962;Gillespie et al, 1962). The time course of antihypertensive effect does not correlate with the rapid serum half-life of methyldopa (1-2 h); however, it may correlate with a second phase serum half-life of methyldopa and/or metabolites (Stenbeak et al, 1977). This second phase halflife may reflect methyldopa metabolites leaving the site of action in the brain.…”

Section: Discussionsupporting

confidence: 84%

See 1 more Smart Citation

Duration of effect of single daily dose methyldopa therapy.

Jm¹,

Orozco-Gonzalez²,

Polak³

et al. 1982

Brit J Clinical Pharma

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1 Methyldopa has a short plasma half‐life, but longer duration of antihypertensive effect. A single bedtime dose of methyldopa has been recommended to improve compliance and decrease side effects. 2 This double‐blind crossover study was designed to determine the duration of antihypertensive effect of methyldopa by comparing hourly supine and standing blood pressures, throughout the day during placebo, single morning dose, and single evening dose methyldopa therapy in 10 patients. The major side effects, drowsiness and dry mouth were assessed by visual analogue scale. Exercise blood pressures were measured 6, 12, 18 and 24 h after the dose. 3 The antihypertensive effect of methyldopa peaked after 6‐9 h and declined thereafter with a half‐life of approximately 10 h. Little antihypertensive effect remained 24‐26 h after the dose. The time course of the reduction in blood pressure during exercise and of the major side effects paralleled the antihypertensive effects. 4 The results suggest that the duration of antihypertensive effect of methyldopa is long enough to permit twice daily dosing, but that single daily dosing cannot be recommended for most patients. The study illustrates the importance of knowing the time of the last methyldopa dose when assessing blood pressure measurements in patients taking the drug.

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Section: Discussionsupporting

confidence: 84%

“…Methyldopa has a short elimination half-life (Kwan et al, 1976;Stenbeak et al, 1977) and was originally administered three or four times daily. However, the necessity of this inconvenient dosing regimen has been brought into question.…”

Section: Introductionmentioning

confidence: 99%

Duration of effect of single daily dose methyldopa therapy.

Jm¹,

Orozco-Gonzalez²,

Polak³

et al. 1982

Brit J Clinical Pharma

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“…This conjugation therefore most probably occurs in the intestinal mucosal cells (Saavendra et aI., 1975;Stenbaek et a!., 1977). Besides O-sulphate, small amounts of other acid-labile conjugates are Sjoerdsma et aI., 1963).…”

Section: Metabolismmentioning

confidence: 96%

“…ous administration (Kwan et a!., 1976;Myhre et a!., 1972b;Stenbaek et at., 1977). Therefore, plasma samples from the 2 routes of administration show a marked difference in the amount of methyldopa present as conjugates.…”

Section: Absorption and Bioavailabilitymentioning

confidence: 96%

Clinical Pharmacokinetics of Methyldopa

Myhre

Rugstad

Hansen

1982

Clinical Pharmacokinetics

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Absorption of methyldopa from the gastrointestinal tract is incomplete and variable; bioavailability after oral administration is about 25% (range 8 to 62%). The average time to reach maximum plasma concentration (tmax) [chemically determined] is 2 hours, when the maximum plasma concentration of active drug accounts for 50% of the radioactivity, the remainder representing various metabolites. Physicochemical determination of methyldopa shows that bi-phasic elimination occurs after both intravenous and oral administration, the half-life of the alpha-phase being 0.21 hours (range 0.16 to 0.26 hours) and of the beta-phase 1.28 hours (range 1.02 to 1.69 hours) in normal subjects. Methyldopa is less than 15% protein bound, whereas the primary metabolite, which most probably is the O-sulphate, is about 50% protein bound. The apparent volume of distribution in the central compartment is about 0.23L/kg (range 0.19 to 0.32L/kg), and the total volume of distribution (calculated as Vdarea) is about 0.60L/kg (range 0.41 to 0.72L/kg) in healthy volunteers. Acid-labile conjugates are formed after oral administration. These acid-labile conjugates, in particular the O-sulphate, are probably formed in the intestinal cells, since they are detected in very small amounts after intravenous administration. Additionally, there is a rapid formation of partly unidentified metabolites after both intravenous and oral administration. After intravenous administration the quantitatively most prominent metabolites are methyldopamine and the glucuronide of dihydroxyphenylacetone, but traces of 5 or 6 other metabolites have also been found and identified. These metabolites are probably formed in the liver, but the complete metabolic pattern is still unknown. The renal clearance of methyldopa (95 ml/min/m2) is more than 50% higher than the endogenous creatinine clearance. Renal excretion of some metabolites is slower. Extrarenal elimination accounts for about 50% of the total body clearance of the drug. Renal excretion is very low in patients with renal failure, resulting in accumulation of both active drug and, in particular, its metabolites. There is a marked accumulation of unidentified metabolites in renal failure patients, which possibly explains the strong and prolonged hypotensive action of methyldopa in these patients.

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“…Some compounds, including phenol itself at high concentrations and paracetamol can serve as substrates for both the thermolabile and thermostable forms of the enzyme (Reiter & Weinshilboum, 1981, 1982. Although sulphate conjugation of MD catalyzed by PST is a major catabolic pathway for MD (Myhre et al, 1972;Saavedra et al, 1975;Stenboek et al, 1977), it is not known whether MD and its amine metabolites are substrates for one or both forms of platelet PST. The present study was designed to determine whether MD, a-methyldopamine (MDA) and a-methylnoradrenaline (MNA) were substrates for the thermolabile, the thermostable or both forms of human platelet PST.…”

mentioning

confidence: 99%

alpha‐Methyldopa, alpha‐methyldopamine an alpha‐methylnoradrenaline: substrates for the thermolabile form of human platelet phenol sulphotransferase.

Mwaluko¹,

Weinshilboum²

1982

Brit J Clinical Pharma

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1 Sulphate conjugation catalyzed by phenol sulphotransferase (PST) is an important pathway in the catabolism of a-methyldopa (MD). Variations in PST activity in an easily obtained tissue such as the human platelet might reflect individual differences in the sulphate conjugation of MD in other organs and tissues. There are at least two forms of human platelet PST, a thermolabile form for which dopamine is a substrate and a thermostable form for which low concentrations of phenol can serve as a substrate. 2 MD, a-methyldopamine (MDA) and a-methylnoradrenaline (MNA) were tested as substrates for human platelet PST. All three were substrates for the thermolabile form of the enzyme and none were substrates for the thermostable form of PST. Apparent Michaelis-Menten (&,,) values for MD, MDA and MNA were 5.5, 0.014 and 0.28 mn, respectively. Apparent Km values for 3'-phosphoadenosine-5'-phosphosulphate, the sulphate donor for the reaction, were 0.08, 0.13 and 0.10 ,uM, respectively, for the three catechol substrates. The pH optima for the reaction were 7.5 for MD and 6.5 for both MDA and MNA. 3 When platelet homogenates from 20 individual subjects were tested, there were significant correlations between PST activities measured with dopamine and those measured with MD, MDA and MNA (r = 0.54, 0.98 and 0.93, P <0.02, <0.001, and <0.001, respectively), but not between activities measured with low concentrations of phenol and those measured with MD, MDA and MNA (r = 0.021, 0.045 and 0.046, respectively). These results were also compatible with the conclusion that MD, MDA and MNA were substrates for the thermolabile form of platelet PST. 4 These observations will make it possible to test the hypothesis that variations in the activity of the thermolabile form of platelet PST may reflect individual differences in the sulphate conjugation of MD, MDA and MNA.

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Pharmacokinetics of methyldopa in healthy man

Cited by 26 publications

References 11 publications

Duration of effect of single daily dose methyldopa therapy.

Duration of effect of single daily dose methyldopa therapy.

Clinical Pharmacokinetics of Methyldopa

alpha‐Methyldopa, alpha‐methyldopamine an alpha‐methylnoradrenaline: substrates for the thermolabile form of human platelet phenol sulphotransferase.

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