Effect of plasma levels of large neutral amino acids and degree of parkinsonism on the blood‐to‐brain transport of levodopa in naive and MPTP parkinsonian monkeys

Abstract

We investigated the transport of levodopa from blood to brain in control and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) parkinsonian monkeys by using intracerebral microdialysis. The degree of parkinsonism was established by the monkey's clinical score and its postmortem striatal dopamine level. We administered levodopa plus carbidopa either orally or by intravenous injection. We estimated the blood-to-brain transport of levodopa as the ratio of its concentration in the brain's extracellular fluid to that in arterial plasma. This ratio was reduced in the MPTP parkinsonian monkeys, and we found an inverse relationship between the monkeys' ability to transport levodopa from blood to brain and their degree of parkinsonism. The oral administration of a high-protein meal or the intravenous infusion of large neutral amino acids before the administration of the levodopa plus carbidopa reduced the transport of levodopa into the brain, as measured by microdialysate collected from the striatum. We found that in two animals an intraperitoneal injection of the beta-adrenergic agonist isoproterenol increased the blood-to-brain transport of levodopa. Pharmacologic manipulation of the transport of levodopa from blood to brain may offer a new strategy for the treatment of Parkinson's disease.

Levodopa in Parkinson’s Disease: A Review of Population Pharmacokinetics/Pharmacodynamics Analysis

“…It crosses the blood-brain barrier but does not bind to the dopamine receptor and has no recognised intrinsic antiparkinsonian activity. Nevertheless, 3OMD can competitively inhibit transport of levodopa [53]. The role of 3OMD in the pharmacokinetic-pharmacodynamic of levodopa has been investigated with concomitant administration of specific catechol-0-methyltransferase (entacapone, tolcapone), and may be helpful in elucidating the relationship between plasma concentrations of levodopa and its effects [35,38,39].…”

Development of a Computational Approach to Predict Blood-Brain Barrier Permeability

“…We refined the logPS model to predict the BBB permeability for 23 substrates that penetrate BBB primarily through a passive diffusion mechanism. Phenylalanine and levodopa have been reported as good substrates of system L for large neutral amino acids, an uptake transport system at BBB (Wade and Katzman, 1975;Momma et al, 1987;Alexander et al, 1994;Sanchez del Pino et al, 1995). According to BB KO /BB WT ratio Ͼ 2, five compounds in our data set have been reported as possible substrates for P-gp, an Gratton et al (1997) …”

Docosahexaenoic acid reduces levodopa‐induced dyskinesias in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine monkeys

“…Because L-dopa is an amino acid derivative, the possibility that protein-rich meal ingestion alters oral L-dopa absorption and brain bioavailability has been documented. 23,24 DHA is an essential polyunsaturated fatty acid that is rapidly taken up by the body and rapidly incorporated into triglycerides in the blood circulation. Although the active transport of DHA into the brain is not well understood, strong evidence indicate that DHA easily enters into the brain.…”