Bound, free, and total l-dopa measurement in plasma of Parkinson’s disease patients

  • Thomas MüllerEmail author
  • Hans Michael Thiede
Neurology and Preclinical Neurological Studies - Original Article


Peaks and troughs of levodopa in plasma contribute to pulsatile postsynaptic dopamine receptor stimulation in patients with Parkinson’s disease. Measurement of levodopa plasma levels mostly only considers the total levodopa plasma concentration. Objectives were to determine bound, free, and total plasma levodopa and to investigate their correlations to each other. We employed reversed-phase high-performance liquid chromatography combined with electrochemical detection. Bound levodopa was computed as difference between total and free l-dopa values. Close correlations between free and total (R = 0.93, p < 0.0001), bound and total (R = 0.91, p < 0.0001) plasma levodopa appeared. A considerable variability of levodopa concentrations occurred. The ratio between bound and free levodopa did not differ in patients with a higher and lower oral daily levodopa dosing. Free, bound, and total levodopa plasma levels are closely related. Estimation of the total levodopa level only seems to be meaningful.


Levodopa Plasma concentrations Parkinson’s disease 



  1. Arabia G, Zappia M, Bosco D, Crescibene L, Bagala A, Bastone L, Caracciolo M, Scornaienghi M, Quattrone A (2002) Body weight, levodopa pharmacokinetics and dyskinesia in Parkinson’s disease. Neurol Sci 23(Suppl 2):S53–S54CrossRefGoogle Scholar
  2. Buhmann C, Bihler M, Emich K, Hidding U, Potter-Nerger M, Gerloff C, Niessen A, Flugel T, Koseki JC, Nienstedt JC, Pflug C (2019) Pill swallowing in Parkinson’s disease: a prospective study based on flexible endoscopic evaluation of swallowing. Parkinsonism Relat Disord 62:51–56CrossRefGoogle Scholar
  3. Kurlan R, Rubin AJ, Miller C, Rivera-Calimlim L, Clarke A, Shoulson I (1986) Duodenal delivery of levodopa for on-off fluctuations in parkinsonism: preliminary observations. Ann Neurol 20:262–265CrossRefGoogle Scholar
  4. Kurlan R, Rothfield KP, Woodward WR, Nutt JG, Miller C, Lichter D, Shoulson I (1988) Erratic gastric emptying of levodopa may cause “random” fluctuations of parkinsonian mobility. Neurology 38:419–421CrossRefGoogle Scholar
  5. Meiler B, Andrich J, Müller T (2008) Rapid switch from oral antiparkinsonian combination drug therapy to duodenal levodopa infusion. Mov Disord 23:145–146CrossRefGoogle Scholar
  6. Muhlack S, Woitalla D, Welnic J, Twiehaus S, Przuntek H, Müller T (2004) Chronic levodopa intake increases levodopa plasma bioavailability in patients with Parkinson’s disease. Neurosci Lett 363:284–287CrossRefGoogle Scholar
  7. Müller WE (1985) A common single binding site for many psychotropic drugs on human alpha 1-acid glycoprotein. Therapeutically relevant observation? Pharmacopsychiatry 18:257–258CrossRefGoogle Scholar
  8. Müller T (2010) The impact of COMT-inhibition on gastrointestinal Levodopa absorption in Patients with Parkinson’s disease. Clin Med Insights 2:155–168Google Scholar
  9. Müller T (2013) Pharmacokinetic considerations for the use of levodopa in the treatment of Parkinson disease: focus on levodopa/carbidopa/entacapone for treatment of levodopa-associated motor complications. Clin Neuropharmacol 36:84–91CrossRefGoogle Scholar
  10. Müller T, Möhr JD (2018) Long-term management of Parkinson’s disease using levodopa combinations. Expert Opin Pharmacother 19:1003–1011CrossRefGoogle Scholar
  11. Müller T, Woitalla D, Saft C, Kuhn W (2000) Levodopa in plasma correlates with body weight of parkinsonian patients. Parkinsonism Relat Disord 6:171–173CrossRefGoogle Scholar
  12. Müller T, Erdmann C, Bremen D, Schmidt WE, Muhlack S, Woitalla D, Goetze O (2006a) Impact of gastric emptying on levodopa pharmacokinetics in Parkinson disease patients. Clin Neuropharmacol 29:61–67CrossRefGoogle Scholar
  13. Müller T, Erdmann C, Muhlack S, Bremen D, Przuntek H, Goetze O, Woitalla D (2006b) Pharmacokinetic behaviour of levodopa and 3-O-methyldopa after repeat administration of levodopa/carbidopa with and without entacapone in patients with Parkinson’s disease. J Neural Transm 113:1441–1448CrossRefGoogle Scholar
  14. Nyholm D (2006) Enteral levodopa/carbidopa gel infusion for the treatment of motor fluctuations and dyskinesias in advanced Parkinson’s disease. Expert Rev Neurother 6:1403–1411CrossRefGoogle Scholar
  15. Pincus JH, Barry KM (1987) Plasma levels of amino acids correlate with motor fluctuations in parkinsonism. Arch Neurol 44:1006–1009CrossRefGoogle Scholar
  16. Ramot Y, Nyska A, Maronpot RR, Shaltiel-Karyo R, Tsarfati Y, Manno RA, Sacco G, Yacoby-Zeevi O (2017) Ninety-day local tolerability and toxicity study of ND0612, a novel formulation of levodopa/carbidopa, administered by subcutaneous continuous infusion in minipigs. Toxicol Pathol 45:764–773CrossRefGoogle Scholar
  17. Ribeiro RP, Gasparetto JC, de Oliveira V, Guimaraes de Francisco TM, Martins CA, Cardoso MA, Pontarolo R, de Carvalho KA (2015) Simultaneous determination of levodopa, carbidopa, entacapone, tolcapone, 3-O-methyldopa and dopamine in human plasma by an HPLC-MS/MS method. Bioanalysis 7:207–220CrossRefGoogle Scholar
  18. Rose S, Jenner P, Marsden CD (1994) Chronic administration does not alter the accumulation of l-dopa into muscle. Mov Disord 9:167–172CrossRefGoogle Scholar
  19. Tuomainen P, Männisto PT (1997) Optimization of the hydrolysis of conjugated l-DOPA, dopamine and dihydroxyphenylacetic acid in human urine for assay by high-performance liquid chromatography with electrochemical detection. Eur J Clin Chem Clin Biochem 35:229–235Google Scholar
  20. van Kessel SP, Frye AK, El-Gendy AO, Castejon M, Keshavarzian A, van Dijk G, El Aidy S (2019) Gut bacterial tyrosine decarboxylases restrict levels of levodopa in the treatment of Parkinson’s disease. Nat Commun 10:310CrossRefGoogle Scholar
  21. Weidinger S, Müller T, Schwarzfischer F, Cleve H (1987) Three new orosomucoid (ORM) variants revealed by isoelectric focusing and print immunofixation. Hum Genet 77:286–288CrossRefGoogle Scholar
  22. Yeggoni DP, Subramanyam R (2014) Binding studies of l-3,4-dihydroxyphenylalanine with human serum albumin. Mol BioSyst 10:3101–3110CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of NeurologySt. Joseph Hospital Berlin-WeißenseeBerlinGermany
  2. 2.Thanares GmbHPotsdamGermany

Personalised recommendations