Journal of Neurology

, Volume 257, Supplement 2, pp 253–261 | Cite as

Pharmacokinetics of levodopa



This paper reviews the clinically relevant determinants of levodopa peripheral pharmacokinetics and main observed changes in the levodopa concentration–effect relationship with Parkinson’s disease (PD) progression. Available clinically practical strategies to optimise levodopa pharmacokinetics and pharmacodynamics are briefly discussed. Levodopa shows particular pharmacokinetics including an extensive presystemic metabolism, overcome by the combined use of extracerebral inhibitors of the enzyme l-amino acid decarboxylase and rapid absorption in the proximal small bowel by a saturable facilitated transport system shared with other large neutral amino acids. Drug transport from plasma to the brain is mediated by the same carriers operating in the intestinal mucosa. The main strategies to assure reproducibility of both intestinal absorption and delivery to the brain, and the clinical effect include standardization of levodopa dosing with respect to meal times and a controlled dietary protein intake. Levodopa plasma half-life is very short, resulting in marked plasma drug concentration fluctuations which are matched, as the disease progresses, to swings in the therapeutic response (“wearing-off” phenomena). “Wearing-off” phenomena can also be associated, at the more advanced disease stages, with a “negative”, both parkinsonism-exacerbating and dyskinetic effect of levodopa at low, subtherapeutic plasma concentrations. Dyskinesias may also be related to high-levodopa, excessive plasma concentrations. Recognition of the different levodopa toxic response patterns can be difficult on a clinical basis alone and simultaneous monitoring of the levodopa concentration–effect relationship may prove useful to disclose the underlying mechanism and in planning the correct management. Clinically practical strategies to optimise levodopa pharmacokinetics, and possibly its therapeutic response, include liquid drug solutions, controlled release formulations and the use of inhibitors of levodopa metabolism. Unfortunately, these attempts have proved so far only partly successful, due to the complex alterations in cerebral levodopa kinetics which accompany the progressive degeneration of the nigrostriatal dopaminergic system in PD patients.


Levodopa Pharmacokinetics Pharmacodynamics Parkinson’s disease 



The authors reused part of the content of a their previously published article [13], with permission from Adis, a Wolter Kluwer business (©Adis Data Information BV. 1996. All rights reserved).

Conflict of interest

There is no conflict of interest to declare.


  1. 1.
    Astarloa R, Mena MA, Sanchez V, de la Vega L, de Yebenes JG (1992) Clinical pharmacokinetic effects of a diet rich of insoluble fiber on Parkinson disease. Clin Neuropharmacol 15:375–380CrossRefPubMedGoogle Scholar
  2. 2.
    Baruzzi A, Contin M, Riva R, Procaccianti G, Albani F, Tonello C, Zoni E, Martinelli P (1987) Influence of meal ingestion time on pharmacokinetics of orally administered levodopa in Parkinsonian patients. Clin Neuropharmacol 10:527–537CrossRefPubMedGoogle Scholar
  3. 3.
    Carter JH, Nutt JG, Woodward WR (1992) The effect of exercise on levodopa absorption. Neurology 2:2042–2045Google Scholar
  4. 4.
    Cedarbaum JM (1989) The promise and limitations of controlled-release oral levodopa administration. Clin Neuropharmacol 12:147–166CrossRefPubMedGoogle Scholar
  5. 5.
    Committee on Dietary Allowances Food and Nutrition Board (ed) (1989) Recommended dietary allowances. National Academy Press, Washington, DCGoogle Scholar
  6. 6.
    Contin M, Riva R, Martinelli P, Procaccianti G, Cortelli P, Avoni P, Baruzzi A (1990) Response to a standard oral levodopa test in Parkinsonian patients with and without motor fluctuations. Clin Neuropharmacol 13:19–28CrossRefPubMedGoogle Scholar
  7. 7.
    Contin M, Riva R, Martinelli P, Procaccianti G, Albani F, Baruzzi A (1991) Combined levodopa-anticholinergic therapy in the treatment of Parkinson’s disease: effect on levodopa bioavailability. Clin Neuropharmacol 14:148–155CrossRefPubMedGoogle Scholar
  8. 8.
    Contin M, Riva R, Martinelli P, Albani F, Baruzzi A (1991) Effect of age on the pharmacokinetics of oral levodopa in patients with Parkinson’s disease. Eur J Clin Pharmacol 41:463–466CrossRefPubMedGoogle Scholar
  9. 9.
    Contin M, Riva R, Martinelli P, Baruzzi A (1992) Kinetic–dynamic relationship of oral levodopa: possible biphasic response after sequential doses in Parkinson’s disease. Mov Disord 7:244–248CrossRefPubMedGoogle Scholar
  10. 10.
    Contin M, Riva R, Martinelli P, Cortelli P, Albani F, Baruzzi A (1993) Pharmacodynamic modeling of oral levodopa: clinical application in Parkinson’s disease. Neurology 43:367–371PubMedGoogle Scholar
  11. 11.
    Contin M, Riva R, Martinelli P, Cortelli P, Albani F, Baruzzi A (1994) Longitudinal monitoring of the levodopa concentration–effect relationship in Parkinson’s disease. Neurology 44:1287–1292PubMedGoogle Scholar
  12. 12.
    Contin M, Riva R, Martinelli P, Triggs EJ, Albani F, Baruzzi A (1996) The rate of motor response to oral levodopa and the clinical progression of Parkinson’s disease. Neurology 46:1055–1058PubMedGoogle Scholar
  13. 13.
    Contin M, Riva R, Albani F, Baruzzi A (1996) Pharmacokinetic optimisation in the treatment of Parkinson’s disease. Clin Pharmacokinet 30:463–481CrossRefPubMedGoogle Scholar
  14. 14.
    Contin M, Riva R, Martinelli P, Cortelli P, Albani F, Baruzzi A (1999) Concentration–effect relationship of levodopa-benserazide dispersible formulation versus standard form in the treatment of complicated motor response fluctuations in Parkinson’s disease. Clin Neuropharmacol 22:351–355PubMedGoogle Scholar
  15. 15.
    Contin M, Riva R, Martinelli P, Albani F, Avoni A, Baruzzi A (2001) Levodopa therapy monitoring in patients with Parkinson disease: a kinetic–dynamic approach. Ther Drug Monit 23:621–629CrossRefPubMedGoogle Scholar
  16. 16.
    Contin M, Martinelli P, Scaglione C, Avoni P, Albani F, Riva R, Baruzzi A (2008) The effect of entacapone on levodopa rate of absorption and latency to motor response in patients with Parkinson disease. Clin Neuropharmacol 31:267–271CrossRefPubMedGoogle Scholar
  17. 17.
    Deleu D, Jacob P, Chand P, Sarre S, Colwell A (2006) Effects of caffeine on levodopa pharmacokinetics and pharmacodynamics in Parkinson disease. Neurology 12:897–898CrossRefGoogle Scholar
  18. 18.
    Dingemanse J, Jorga K, Zurcher G, Schmitt M, Sedek G, Da Prada M, Van Brummelen P (1995) Pharmacokinetic–pharmacodynamic interaction between the COMT inhibitor tolcapone and single-dose levodopa. Br J Clin Pharmacol 40:253–262PubMedGoogle Scholar
  19. 19.
    Fabbrini G, Juncos JL, Mouradian MM, Serrati C, Chase TN (1987) Levodopa pharmacokinetic mechanisms and motor fluctuations in Parkinson’s disease. Ann Neurol 21:370–376CrossRefPubMedGoogle Scholar
  20. 20.
    Fabbrini G, Mouradian MM, Juncos JL, Schlegel J, Mohr E, Chase TN (1988) Motor fluctuations in Parkinson’s disease: central pathophysiological mechanisms, part I. Ann Neurol 24:366–371CrossRefPubMedGoogle Scholar
  21. 21.
    Gancher ST, Nutt JG, Woodward WR (1987) Peripheral pharmacokinetics of levodopa in untreated, stable and fluctuating Parkinsonian patients. Neurology 37:940–944PubMedGoogle Scholar
  22. 22.
    Guldberg HC, Marsden CA (1975) Catechol-O-methyl transferase: pharmacological aspects and physiological role. Pharmacol Rev 27:135–206PubMedGoogle Scholar
  23. 23.
    Guttman M, Leger G, Cedarbaum JM, Reches A, Woodward W, Evans A, Diksic M, Gjedde A (1992) 3-O-methyldopa administration does not alter fluorodopa transport into the brain. Ann Neurol 31:638–643CrossRefPubMedGoogle Scholar
  24. 24.
    Harder S, Baas H, Rietbrock S (1995) Concentration–effect relationship of levodopa in patients with Parkinson’s disease. Clin Pharmacokinet 29:243–256CrossRefPubMedGoogle Scholar
  25. 25.
    Harder S, Baas H, Bergemann N, Demisch L, Rietbrock S (1995) Concentration–effect relationship of levodopa in patients with Parkinson’s disease after oral administration of an immediate release and a controlled release formulation. Br J Clin Pharmacol 39:39–44PubMedGoogle Scholar
  26. 26.
    Juncos JL, Fabbrini G, Mouradian MM, Serrati C, Chase TN (1987) Dietary influences on the antiparkinsonian response to levodopa. Arch Neurol 44:1003–1005PubMedGoogle Scholar
  27. 27.
    Kaakkola S (2000) Clinical pharmacology, therapeutic use and potential of COMT inhibitors in Parkinson’s disease. Drugs 59:1233–1250CrossRefPubMedGoogle Scholar
  28. 28.
    Kish SJ, Shannak K, Hornykiewicz O (1988) Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson’s disease: pathophysiologic and clinical implications. N Engl J Med 318:876–881CrossRefPubMedGoogle Scholar
  29. 29.
    Kompoliti K, Adler CH, Raman MS, Pincus JH, Leibowitz MT, Ferry JJ, Blasucci L, Caviness JN, Leurgans S, Chase WM, Yones LC, Tan E, Carvey P, Goetz CG (2002) Gender and pramipexole effects on levodopa pharmacokinetics and pharmacodynamics. Neurology 58:1418–1422PubMedGoogle Scholar
  30. 30.
    Kurlan R, Nutt JG, Woodward WR, Rothfield K, Lichter D, Miller C, Carter JH, Shoulson I (1988) Duodenal and gastric delivery of levodopa in Parkinsonism. Ann Neurol 23:589–595CrossRefPubMedGoogle Scholar
  31. 31.
    Leenders KL, Poewe WH, Palmer AJ, Brenton DP, Frackowiak RS (1986) Inhibition of l-(18F) fluorodopa uptake into human brain by amino acids demonstrated by positron emission tomography. Ann Neurol 20:258–262CrossRefPubMedGoogle Scholar
  32. 32.
    Martinelli P, Contin M, Scaglione C, Riva R, Albani F, Baruzzi A (2003) Levodopa pharmacokinetics and dyskinesias: are there sex-related differences? Neurol Sci 24:192–193CrossRefPubMedGoogle Scholar
  33. 33.
    Morgan JP, Rivera-Calimlim L, Messiha F, Sundaresan PR, Trabert N (1975) Imipramine-mediated interference with levodopa absorption from the gastrointestinal tract in man. Neurology 25:1029–1034PubMedGoogle Scholar
  34. 34.
    Muhlack S, Welnic J, Woitalla D, Muller T (2007) Exercise improves efficacy of levodopa in patients with Parkinson’s disease. Mov Disord 15:427–430CrossRefGoogle Scholar
  35. 35.
    Nutt JG, Fellman JH (1984) Pharmacokinetics of levodopa. Clin Neuropharmacol 7:35–49CrossRefPubMedGoogle Scholar
  36. 36.
    Nutt JG, Woodward WR, Hammerstad JP, Carter JH, Anderson JL (1984) The “on-off” phenomenon in Parkinson’s disease. Relation to levodopa absorption and transport. N Engl J Med 310:483–488CrossRefPubMedGoogle Scholar
  37. 37.
    Nutt JG, Woodward WR (1986) Levodopa pharmacokinetics and pharmacodynamics in fluctuating parkinsonian patients. Neurology 36:739–744PubMedGoogle Scholar
  38. 38.
    Nutt JG (1987) On–off phenomenon: relation to levodopa pharmacokinetics and pharmacodynamics. Ann Neurol 22:535–540CrossRefPubMedGoogle Scholar
  39. 39.
    Nutt JG, Woodward WR, Gancher ST, Merrick D (1987) 3-O-methyldopa and the response to levodopa in Parkinson’s disease. Ann Neurol 21:584–588CrossRefPubMedGoogle Scholar
  40. 40.
    Nutt JG, Gancher ST, Woodward WR (1988) Does an inhibitory action of levodopa contribute to motor fluctuations? Neurology 38:1553–1557PubMedGoogle Scholar
  41. 41.
    Nutt JG (1990) Levodopa-induced dyskinesia: review, observations, and speculations. Neurology 40:340–345PubMedGoogle Scholar
  42. 42.
    Nutt JG, Holford NHG (1996) The response to levodopa in Parkinson’s disease: imposing pharmacological law and order. Ann Neurol 39:561–573CrossRefPubMedGoogle Scholar
  43. 43.
    Nutt JG, Carter JH, Lea ES, Sexton GJ (2002) Evolution of the response to levodopa during the first 4 years of therapy. Ann Neurol 51:686–693CrossRefPubMedGoogle Scholar
  44. 44.
    Nyholm D (2006) Pharmacokinetic optimisation in the treatment of Parkinson ‘s Disease. An update. Clin Pharmacokinet 45:109–136CrossRefPubMedGoogle Scholar
  45. 45.
    Paalzow GHM, Paalzow LK (1986) l-dopa: how it may exacerbate parkinsonian symptoms. TIPS 9:15–19Google Scholar
  46. 46.
    Pierantozzi M, Pietroiusti A, Brusa L, Galati S, Stefani A, Lunardi G, Fedele E, Sancesario G, Bernardi G, Bergamaschi A, Magrini A, Stanzione P, Galante A (2006) Helicobacter pylori eradication and l-dopa absorption in patients with PD and motor fluctuations. Neurology 66:1824–1829CrossRefPubMedGoogle Scholar
  47. 47.
    Quinn N, Parkes D, Marsden CD (1984) Control of on/off phenomenon by continuous intravenous infusion of levodopa. Neurology 34:1131–1136PubMedGoogle Scholar
  48. 48.
    Reuter I, Harder S, Engelhardt M, Baas H (2000) The effect of exercise on pharmacokinetics and pharmacodynamics of levodopa. Mov Disord 15:862–868CrossRefPubMedGoogle Scholar
  49. 49.
    Rivera-Calimlim L, Dujovne CA, Morgan JP, Lasagna L, Bianchine JR (1970) l-dopa treatment failure: explanation and correction. Br Med J 4:93–94CrossRefPubMedGoogle Scholar
  50. 50.
    Sage JI, Schuh L, Heikkila RE, Duvoisin RC (1988) Continuous duodenal infusions of levodopa: plasma concentrations and motor fluctuations in Parkinson’s disease. Clin Neuropharmacol 11:36–44CrossRefPubMedGoogle Scholar
  51. 51.
    Vingerhoets FJ, Snow BJ, Lee CS, Schulzer M, Mak E, Calne DB (1994) Longitudinal fluorodopa positron emission tomographic studies of the evolution of idiopathic parkinsonism. Ann Neurol 36:759–764CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Laboratory of Clinical Neuropharmacology, Department of Neurological Sciences, Neurology ClinicUniversity of BolognaBolognaItaly
  2. 2.Centre for the Study of Extrapyramidal Diseases, Department of Neurological SciencesUniversity of BolognaBolognaItaly

Personalised recommendations