Clinical Pharmacokinetics of Methyldopa
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
Absorption of methyldopa from the gastrointestinal tract is incomplete and variable; bio-availability after oral administration is about 25% (range 8 to 62%). The average lime 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 α-phase being 0.21 hours (range 0.16 to 0.26 hours) and of the β-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 (95ml/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.
- Au, W.Y.W.; Dring, LG.; Grahame-Smith, D.G.; Isaac, P. and Williams, R.T.: The metabolism of 14C-labelled α-methyldopa in normal and hypertensive human subjects. Biochemical Journal 129: 1–10 (1972).
- Barnett, A.J.; Bobik, A.; Carson, V.; Korman, J.S. and McLean, A.J.: Pharmacokinetics of methyldopa. Plasma levels following single intravenous, oral and multiple oral dosage in normotensive and hypertensive subjects. Clinical and Experimental Pharmacology and Physiology 4: 331–339 (1977). CrossRef
- Benestad, C. and Arnold, E.: Biotransformation of methyldopa in man. Submitted for publication (1981).
- Brodwall, E.K.; Myhre, E.; Stanbaek, Ø. and Hansen, T.: The effect of methyldopa on renal function in patients with renal insufficiency. Acta Medical Scandinavica 191: 339–341 (1972).
- Buhs, R.P.: Beck, J.L: Speth, O.C.; Smith, J.L.: Trenner, N.R.; Cannon, P.J. and Laragh, J.H.: The metabolism of methyldopa in hypertensive human subjects. Journal of Pharmacology and Experimental Therapeutics 143: 205–214 (1964).
- Cannon, P.J.; Whitlock, R.T.; Morris, C.; Angers, M. and Laragh, J.H.: Effect of alpha-methyldopa in severe and malignant hypertension. Journal of the American Medical Association 179: 673–681 (1962). CrossRef
- Carlson. A. and Lindquist, M.: In vivo decarboxylation of α-methyldopa and α-methyl-metathyrosine. Acta Physiologica Scandinavica 54: 87–94 (1962). CrossRef
- Cooper, M.J.; O’Dea, R.F. and Mirkin, B.L.: Determination of methyldopa and metabolites in human serum by high-performance liquid chromatography with electrochemical detection. Journal of Chromatography 162: 601–604 (1979). CrossRef
- Dollery, C.T. and Harington, M.: Methyldopa in hypertension. Lancet 1: 759–763 (1962). CrossRef
- Editorial: Treatment of moderate hypertension in pregnancy. British Medical Journal 280: 1483–1484 (1980). CrossRef
- George, C.F.; Higgins, V.; Power, K.J.; Renwick, A.G. and Smith. C.L.: Pharmacokinetics of methyldopa in gastrointestinal disease. British Journal of Clinical Pharmacology 9: 109P–110P (1980). CrossRef
- Gillespie, L.; Oates. J.A.; Crout, J.R. and Sjoerdsma, A.: Clinical and chemical studies with α-methyl-dopa in patients with hypertension. Circulation 25: 281–291 (1962). CrossRef
- Greenblatt, D.J. and Koch-Weser, J.: Clinical pharmacokinetics. New England Journal of Medicine 293: 702–705 (1975). CrossRef
- Henning, M.: Studies on the mode of action of α-methyl-dopa. Acta Physiologica Scandinavica 322 (Suppl.): 1–37 (1969).
- Hess, S.M.; Connamacher, R.H.; Ozaki, M. and Undenfriend, S.: The effects of α-methyl-dopa and α-methyl-metathyrosine on the metabolism of norepinephrine and serotonin in vivo. Journal of Pharmacology and Experimental Therapeutics 134: 129–138 (1961).
- Hunt, J.C.; Strong, C.G.; Harrison, E.G.; Furlow, W.L. and Leary, F.J.: Management of hypertension of renal origin. American Journal of Cardiology 26: 280–288 (1970). CrossRef
- Jones, H.M.R.; Cummings, A.J.; Setchell, K.D.R. and Lawson, A.M.: A study of the disposition of α-methyldopa in newborn infants following its administration to the mother for the treatment of hypertension during pregnancy. British Journal of Clinical Pharmacology 8: 433–440 (1979). CrossRef
- Kaldor, A.; Jurvancz, P.; Domeezky, M.; Sebextyen, K. and Palotas, J.: Enhancement of methyldopa metabolism with barbiturates. British Medical Journal 3: 518–519 (1971). CrossRef
- Kochak, G.M. and Mason, W.D.: Determination of free methyldopa in plasma by high-pressure liquid chromalography and electrochemical detection. Journal of Pharmaceutical Sciences 69: 897–900 (1980). CrossRef
- Kwan, K.E.; Foltz, E.L.; Breault, G.O.; Baer, J.E. and Totaro, J.A.: Pharmacokinetics of methyldopa in man. Journal of Pharmacology and Experimental Therapeutics 198: 264–277 (1976).
- Lawson, D.H.; Gloss, D. and Jick, J.: Adverse reactions to methyldopa with particular reference to hypotension. American Heart Journal 96: 572–579 (1978). CrossRef
- Mohammed, S.; Hanenson, L.B.; Magenheim, H.G. and Gaffney, T.E.: The effects of alpha-methyldopa on renal function in hypertensive patients. American Heart Journal 76: 21–27 (1968). CrossRef
- Moodley, J.: The management of hypertension in pregnancy. A review. South African Medical Journal 58: 103–109 (1980).
- Myhre, E.; Brodwall, E.K.; Stenbaek, Ø. and Hansen, T.: Plasma turnover of methyldopa in advanced renal failure. Acta Medica Scandinavica 191: 343–347 (1972a).
- Myhre, E.; Stenbaek, Ø.; Brodwall, E. and Hansen, T.: Conjugation of methyldopa in renal failure. Scandinavian Journal of Clinical and Laboratory Investigation 29: 195–199 (1972b). CrossRef
- Myhre, E.; Brodwall, E.K.; Stenbaek, Ø. and Hansen, T.: The renal excretion of methyldopa. Scandinavian Journal of Clinical and Laboratory Investigation 29: 201–204 (1972c). CrossRef
- Myhre, E.; Stenbaek, Ø.; Rugstad, H.E.; Arnold, E. and Hansen, T.: Pharmacokinetics of methyldopa in renal failure and bilaterally nephrectomized patients. Scandinavian Journal of Urology and Nephrology. In press (1981).
- Oates, J.A.; Gillespie, L.; Undenfriend, S. and Sjoerdsma, A.: Decarboxylase inhibition and blood pressure reduction by α-methyl-3.4-dihydroxy-dl-phenylalanine. Science 131: 1890–1891 (1960). CrossRef
- O’Dea, R.F. and Mirkin, B.L.: Metabolic disposition of methyldopa in hypertensive and renal-insufficient children. Clinical Pharmacology and Therapeutics 27: 37–43 (1980). CrossRef
- Onesti, G.; Brest, A.N.; Novack, P.; Kasparian, H. and Mover, J.H.: Pharmacodynamic effects of alpha-methyl-dopa in hypertensive subjects. American Heart Journal 67: 32–38 (1964). CrossRef
- Porter, C.C. and Titus, D.C.: Distribution and metabolism of methyldopa in the rat. Journal of Pharmacology and Experimental Therapeutics 139: 77–87 (1963).
- Porter, C.C.; Tataro, J.A. and Burein, A.: The relationship between radioactivity and norephinephrine concentrations in the brains and hearts of mice following administration of labelled methyldopa or 6-hydroxy dopamine. Journal of Pharmacology and Experimental Therapeutics 150: 17–22 (1965).
- Prescott, L.F.; Buhs, R.P.; Beattie, J.O.; Speth, O.C.; Trenner, N.R. and Lasagna, L.: Combined clinical and metabolic study of the effects of alpha-methyldopa on hypertensive patients. Circulation 34: 308–312 (1966). CrossRef
- Saavendra. J.A.; Reid. J.L.; Jordan. W.; Rawlins, M.D. and Dollery, C.T.: Plasma concentration of α-methyldopa and sulphate conjugate after oral administration of methyldopa and intravenous administration of methyldopa and methyldopa hydrochloride ethyl ester. European Journal of Clinical Pharmacology 8: 381–386 (1975). CrossRef
- Schlossmann, K.; Boch, K.D. and Krineberg, G.: Katecholamin-bestimmung im menschlichen Harn wahrend und nach Gabe von Methyldopa. Klinische Wochenschrift 42: 440–443 (1964). CrossRef
- Schrader, K.; Brass, H. and Renner, D.: Pharmakokinetik von α-Methyldopa bei Niereniasuffizienz. Klinische Wochenschrift 49: 1329–1334 (1971). CrossRef
- Sjoerdsma, A.: Vendsalu, A. and Engelman, K.: Studies on the metabolism and mechanism of action of methyldopa. Circulation 28: 492–502 (1963). CrossRef
- Sourkes, T.K.; Murphy, C.F.; Chavez, B. and Zielinska, M.: The action of some α-methyl and other amino acids on cerebral catecholamines. Journal of Neurochemistry 8: 109–115 (1961). CrossRef
- Stenbaek, T.; Myhre, E.; Brodwall, E.K. and Hansen, T.: Hypotensive effect of methyldopa in renal failure associated with hypertension. Acta Medica Scandinavica 191: 333–337 (1971).
- Stenbaek, Ø.; Myhre, E.; Rugstad, H.E.; Arnold, E. and Hansen, T.: Pharmacokinetics of methyldopa in normal man. Journal of Clinical Pharmacology and Therapeutics 12: 117–123 (1977).
- Stenbaek, Ø.; Myhre, E.; Rugstad, H.E.; Arnold, E. and Hansen, T.: The absorption and excretion of methyldopa ingested concomitantly with amino acids or food rich in protein. Acta Pharmacologica et Toxicologica. In press (1981).
- Vickers, S.; Duncan, C.A.; White, S.D.; Breault, C.O.; Royds, R.B.; Schepper, P.J. and Tempero, K.F.: Evaluation of succinimidoethyl and pivaloyloxyethyl esters as progenitors of methyldopa in man, rhesus monkey, dog and rat. Drug Metabolism and Disposition 6: 640–646 (1978).
- Yeh, B.K.; Dayton, P.G. and Waters, W.C.: Removal of alpha-methyldopa (Aldomet) in man by dialysis. Proceedings of the Society for Experimental Biology and Medicine (New York) 135: 840–843 (1970).
- Young, J.A. and Edwards, K.D.G.: Studies on the absorption, metabolism and excretion of methyldopa and other catechols and their influence on amino acid transport in rats. Journal of Pharmacology and Experimental Therapeutics 145: 102–112 (1964).
- Clinical Pharmacokinetics of Methyldopa
Volume 7, Issue 3 , pp 221-233
- Cover Date
- Print ISSN
- Online ISSN
- Springer International Publishing
- Additional Links
- Industry Sectors