The transport of L-6-fluorodopa and its metabolites from blood to cerebrospinal fluid and brain.
The transport of L-6-fluorodopa and its major metabolites from the blood to the brain, cerebrospinal fluid (CSF), and muscle was studied in carbidopa-pretreated cynomolgus monkeys. A bolus intravenous injection of 18F-L-6-fluorodopa was followed by serial positron emission tomography scans and sampling of cisternal CSF and arterial blood. The relative concentrations of L-6-fluorodopa and its metabolites were determined in blood plasma and CSF by high-performance liquid chromatography. Raising the blood concentration of phenylalanine by intraperitoneal injection markedly reduced the accumulation of tracer in the brain. This indicates that L-6-fluorodopa and 3-O-methylfluorodopa, like native L-dopa and its O-methylated derivative, are transported at the brain capillary by the large neutral amino acid carrier-mediated system, which is subject to saturation and competition by other large neutral amino acids (such as phenylalanine) at physiological plasma concentrations. In contrast, administration of phenylalanine had no effect on the accumulation of tracer either in muscle, or as L-6-fluorodopa and 3-O-methylfluorodopa, in CSF. This suggests that the transport of L-dopa and its derivatives at the blood-CSF barrier differs from the transport at the blood-brain barrier and also that measurement of CSF L-dopa is not a good index of the transport and pharmacokinetics of L-dopa in the brain. However, the effect of phenylalanine administration in reducing the concentration of fluorohomovanillic acid in the CSF suggests that the concentration of homovanillic acid in the CSF is an accurate reflection of dopamine turnover in the brain.
Hammerstad
J P
JP
Neurodegenerative Disorders Centre, University of British Columbia, Vancouver, Canada.
Pate
B D
BD
Hewitt
K A
KA
Chan
G L
GL
Ruth
T J
TJ
Calne
D B
DB
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D001923:Brain Chemistry; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives* / Q000032:analysis / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism; D005462:Fluorine Radioisotopes; D006719:Homovanillic Acid / Q000134:cerebrospinal fluid / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D010649:Phenylalanine / Q000378:metabolism / Q000494:pharmacology; D014055:Tomography, Emission-Computed
D000596:Amino Acids; D005462:Fluorine Radioisotopes; C055151:3-O-methyl-6-fluoro-dopa; C055153:6-fluorohomovanillic acid; C043437:fluorodopa F 18; D010649:Phenylalanine; D004295:Dihydroxyphenylalanine; D006719:Homovanillic Acid