Variable Absorption of Carbidopa Affects Both Peripheral and Central Levodopa Metabolism

Autor: Raymon Durso, Barbara A. Evans, Thomas R. Browne, Ephraim G. Josephs, H. H. Fernandez, George K. Szabo, James E. Evans
Rok vydání: 2000
Předmět:
Zdroj: The Journal of Clinical Pharmacology. 40:854-860
ISSN: 0091-2700
DOI: 10.1177/00912700022009585
Popis: Carbidopa (CD), a competitive inhibitor of aromatic l-amino acid decarboxylase that does not cross the blood-brain barrier, is routinely administered with levodopa (LD) to patients with Parkinson disease (PD) to reduce the peripheral decarboxylation of LD to dopamine. Using a stable isotope-labeled form of LD, the authors examined in 9 PD patients the effects of variable CD absorption on peripheral and central LD metabolism. Subjects were administered orally 50 mg of CD followed in 1 hour by a slow bolus intravenous infusion of 150 mg stable isotope-labeled LD (ring 1',2',3',4',5',6'-13C). Eight patients underwent a lumbar puncture 6 hours following the infusion. Blood and cerebrospinal fluid (CSF) samples were analyzed for labeled and unlabeled metabolites using a combination of high-performance liquid chromatography and mass spectrometry. When patients were divided into "slow" and "rapid" CD absorption groups, significantly greater peripheral LD decarboxylation (as measured by area under the curve [AUC]-labeled serum HVA) was noted in the poor absorbers (p = 0.05, Mann-Whitney U test). Elimination half-lives for serum LD did not differ between groups, suggesting a further capacity for decarboxylation inhibition in the "rapid" absorbers. A significant correlation between AUC serum CD and percent-labeled HVA in CSF was found for all patients (R = 0.786, p = 0.02). "Rapid" as compared to "slow" CD absorbers had significantly more percent-labeled CSF HVA (60 vs. 49, p = 0.02, Mann-Whitney U test), indicating greater central-labeled DA production in the better CD absorbers. The data suggest that peripheral aromatic l-amino acid decarboxylase activity is not saturated at CD doses used in current practice. The authors believe that future studies to better examine a dose dependence of CD on peripheral LD decarboxylation and LD brain uptake are warranted.
Databáze: OpenAIRE
Externí odkaz: