Variable absorption of carbidopa affects both peripheral and central levodopa metabolism.
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.
Department of Neurology, Boston Veterans Administration Medical Center, Massachusetts, USA.
R
R
Durso
J E
JE
Evans
E
E
Josephs
G
G
Szabo
B
B
Evans
H H
HH
Fernandez
T R
TR
Browne
D000042:Absorption; D000328:Adult; D000368:Aged; D000978:Antiparkinson Agents / Q000493:pharmacokinetics*; D001921:Brain / Q000378:metabolism*; D002230:Carbidopa / Q000493:pharmacokinetics*; D002648:Child; D006719:Homovanillic Acid / Q000493:pharmacokinetics; D006801:Humans; D007980:Levodopa / Q000493:pharmacokinetics*; D008875:Middle Aged
D000978:Antiparkinson Agents; D007980:Levodopa; D002230:Carbidopa; D006719:Homovanillic Acid