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Human pharmacokinetics of L-3,4-dihydroxyphenylalanine studied with microdialysis
Linköping University, Department of Clinical and Experimental Medicine, Neurology . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Neurology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
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1999 (English)In: Clinical Chemistry, ISSN 0009-9147, Vol. 45, no 10, 1813-1820 p.Article in journal (Refereed) Published
Abstract [en]

Background: Intravenous and subcutaneous microdialysis was performed to compare the free concentrations and pharmacokinetics of L-3,4-dihyroxyphenylalanine (L-dopa) in blood and tissue in healthy subjects and in patients with Parkinson disease.

Methods: Nine healthy volunteers and 10 patients with Parkinson disease, stage 1.5–2 according to the Hoehn-Yahr rating scale, took part of the study. In the patient group subcutaneous microdialysis and ordinary blood sampling were performed, whereas in the control group intravenous microdialysis was also performed. Microdialysis samples were collected in fractions of 15 min. The first two fractions were collected for analysis of basal concentrations. A blood sample was also taken. The patients were then given one tablet of Madopar® (100 mg of L-dopa and 25 mg of benserazide), and the microdialysis was continued for another 210 min. Blood samples were obtained at 30-min intervals.

Results: The serum samples gave a significantly higher mean area under the curve (AUC; 491 ± 139 µmol · min/L) than that for intravenous dialysates (235 ± 55.3 µmol · min/L), suggesting a protein binding of 50%. The L-dopa concentrations from the subcutaneous dialysates matched those from the intravenous dialysates, indicating rapid distribution of L-dopa to the tissues.

Conclusions: Parkinsonian patients in early stages of the disease have a pharmacokinetic pattern of free L-dopa similar to that of healthy subjects. Comparison of AUCs from microdialysis with ordinary serum analysis revealed data indicating significant protein binding. Microdialysis is a suitable and easily applied tool in pharmacokinetic studies.

Place, publisher, year, edition, pages
1999. Vol. 45, no 10, 1813-1820 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-13528OAI: oai:DiVA.org:liu-13528DiVA: diva2:20912
Available from: 1999-05-21 Created: 1999-05-21 Last updated: 2009-08-17Bibliographically approved
In thesis
1. Microdialysis as a Tool in Studies of L-Dopa and Metabolites in Malignant Melanoma and Parkinson’s Disease
Open this publication in new window or tab >>Microdialysis as a Tool in Studies of L-Dopa and Metabolites in Malignant Melanoma and Parkinson’s Disease
1999 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A model with human melanoma xenografts transplanted to athymic mice has been adopted for in vivo studies of 5-S-cysteinyldopa (an intermediate pigment metabolite), glutathione, and cysteine. L-Dopa is an intermediate metabolite in pigment formation and is also important in the treatment of Parkinson's disease, and therefore 1 have also studied the pharmacokinetics of this compound.

We were first to describe in vivo microdialysis in melanoma tissue and showed that dialysis membranes of cuprophane or polyamide are suitable for studies of interstitial 5-S-cysteinyldopa and selected thiols. Analytical procedures were also improved for quantitation of 5-S-cysteinyldopa, L-dopa, glutathione, cysteine, and N-acetylcysteine (NAC). In the melanoma xenografts the interstitial concentration of 5-S-cysteinyldopa reflected the high intracellular production of this intermediate metabolite. For in vivo manipulation of glutathione in the melanoma tissue we gave intraperitoneal injection of buthionine sulphoximine to the animals and thus reduced the glutathione concentrations substantially. We showed that restitution of glutathione in melanoma tissue occurs spontaneously and is not much improved by treatment with the cysteine deliverers NAC and L-2-oxothiazolidine-4-carboxylate (OTC). 5-S-Cysteinyldopa was not substantially affected by great variations in glutathione concentrations. Transport of NAC from intraperitoneal injection to melanoma tissue occurred rapidly and deacetylation to cysteine in vivo could be detected soon after NAC injection. In vivo formation of cysteine was slower from OTC than from NAC.

Pharmacokinetic studies of L-dopa in human subjects indicated a slight to moderate protein binding. Plasma free L-dopa had similar elimination T½ as interstitial L-dopa, but in some cases the elimination of total L-dopa was slower. Difficulties in intestinal absorption of L-dopa were revealed by microdialysis in blood and subcutaneous tissue. Studies showed that this was due to delayed emptying of the stomach. L-Dopa intake increased 5-S-cysteinyldopa concentrations in blood within 30 min in patients with Parkinson's disease and a history of melanoma. No melanoma activation occurred during long-term treatment with L-dopa.

Microdialysis is thus a safe and easily applied method for in vivo studies of both pigment metabolites from human melanoma tissue transplanted to nude mice and for pharmacokinetic studies of L-dopa.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 1999. 51 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 588
Keyword
Microdialysis, L-Dopa, Malignant Melanoma, Parkinson's Disease, in vivo
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-5009 (URN)91-7219-332-8 (ISBN)
Public defence
1999-04-09, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 13:00 (English)
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Supervisors
Note
On the day of the public defence the status of the articles IV, V and VI was: Submitted.Available from: 1999-05-21 Created: 1999-05-21 Last updated: 2012-01-24Bibliographically approved

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