Transport systems at the BBB include a neutral amino acid transport system for phenylalanine, leucine, and other neutral amino acids, an acidic amino acid transport system for glutamate and aspartate, a basic amino acid transport system for arg^ine and lysine, and a P-amino acid transport system for P-alanine (4, 52). The design of amino acid analogues could, therefore, be a useful approach in developing effective CNS drugs. Several amino acid mimetic drugs, such as l-dopa, a-methyldopa, a-methyltrepsm, baclofen, gabapentin (neurotin), and phenylalanine mustard, are expected to be taken up by the neutral amino acid transport system (4, 10). 6-[18F]Fluoro-l-dopa (FDOPA) has been used to measure the central dopaminergic function in many species, including humans and monkeys. When the BBB transport of FDOPA was measured in adult monkeys by positron emission tomography scans, it was found to follow Michaelis-Menten kinetics and to be subject to competitive inhibition by the plasma large neutral amino acids (53). Orally administered and endogenous taurine is taken up by the P-alanine transporter at both luminal and abluminal membranes of brain capillary endothelial cells in a Na+- and Cl^-dependent manner (54).
A transport study using primary cultured porcine BCECs suggested the existence of a Na+-independent and saturable (Km = 28 mM) transport system for l-carnitine (55). The proposed luminal transporter for l-carnitine seems to be different from the carnitine transporter OCTN2 cloned recently in our laboratory, because OCTN2 takes up l-camitine in a Na+-dependent manner and exists abundantly in kidney, skeletal muscle, heart, and placenta, but not in brain (56). Currently there is much interest in the pharmacological treatment of patients with Alzheimer's disease, and acyl-l-carnitines are one group of candidate drugs. However, it is unclear whether acyl-l-carnitine is transported across the BBB via a saturable system or by passive diffusion.
Utilization of the hexose transport system for glucose and mannose and the nucleoside transport system for purine bases such as adenine and guanine, but not pyrimidine, is also an attractive strategy for obtaining the efficient delivery of drugs by means of an appropriate chemical modification so that they can be recognized and transported via these transporters (4, 10). The brain-type hexose transporter GLUT-1 has a very large Vmax value. Some l-serinyl-P-d-glycoside analogues of Met5 enkephalin have been shown to be transported across the BBB and produced a marked and long-lasting analgesia after intraperitoneal administration in mice (57). This result implies that GLUT-1 is responsible for transporting these glycopeptides into the CNS and indicates that glycosylation might be a promising way to deliver into the brain drugs with CNS activity but low permeability across the BBB.
Although it has not been established whether the Na+-dependent hexose transporter SGLT is expressed at the BBB, a recent report suggested a participation of SGLT in the BBB transport of cycasin (58). Cycasin, methylazoxy-methanol-d-glucoside, is proposed to be a significant etiologic factor for the prototypical neurodegenerative disorder Western Pacific amyotrophic lateral sclerosis and for Parkinsonism-dementia complex. Cycasin is taken up into primary-cultured bovine BCECs in a dose-dependent manner with maximal uptake at a concentration of 10 |j.M. Since cycasin uptake was significantly inhibited by a-methyl-d-glucoside, a specific analogue for the Na+-dependent glucose transporter, SGLT, as well as by phlorizin (a SGLT inhibitor), replacement of extracellular NaCl with LiCl, and dinitrophenol (an inhibitor of energy metabolism), cycasin is suggested to be transported across the BBB via a Na+ energy-dependent SGLT (58).
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