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Variable Absorption of Carbidopa Affects Both Peripheral and Central Levodopa Metabolism
Author(s) -
Durso R.,
Evans J. E.,
Josephs E.,
Szabo G.,
Evans B.,
Fernandez H. H.,
Browne T. R.
Publication year - 2000
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/00912700022009585
Subject(s) - carbidopa , aromatic l amino acid decarboxylase , chemistry , decarboxylation , cerebrospinal fluid , levodopa , area under the curve , bolus (digestion) , absorption (acoustics) , metabolism , medicine , pharmacology , endocrinology , dopamine , parkinson's disease , biochemistry , physics , disease , acoustics , catalysis
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′‐ 13 C). 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.