Large neutral amino acid transporter enables brain drug delivery via prodrugs.
The blood-brain barrier efficiently controls the entry of drug molecules into the brain. We describe a feasible means to achieve carrier-mediated drug transport into the rat brain via the specific, large neutral amino acid transporter (LAT1) by conjugating a model compound to L-tyrosine. A hydrophilic drug, ketoprofen, that is not a substrate for LAT1 was chosen as a model compound. The mechanism and the kinetics of the brain uptake of the prodrug were determined with an in situ rat brain perfusion technique. The brain uptake of the prodrug was found to be concentration-dependent. In addition, a specific LAT1 inhibitor significantly decreased the brain uptake of the prodrug. Therefore, our results reveal for the first time that a drug-substrate conjugate is able to transport drugs into the brain via LAT1.
Gynther
Mikko
M
Department of Pharmaceutical Chemistry, University of Kuopio, PO Box 1627, FI-70211 Kuopio, Finland. mikko.gynther@uku.fi
Laine
Krista
K
Ropponen
Jarmo
J
Leppänen
Jukka
J
Mannila
Anne
A
Nevalainen
Tapio
T
Savolainen
Jouko
J
Järvinen
Tomi
T
Rautio
Jarkko
J
D000598:Amino Acids, Cyclic / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000378:metabolism*; D002196:Capillaries / Q000378:metabolism; D016503:Drug Delivery Systems; D042783:Endothelial Cells / Q000378:metabolism; D005240:Feasibility Studies; D007660:Ketoprofen / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D027283:Large Neutral Amino Acid-Transporter 1 / Q000378:metabolism*; D007930:Leucine / Q000493:pharmacokinetics; D008297:Male; D010477:Perfusion; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics
C528857:2-amino-3-(4-(2-(3-benzoylphenyl)propionyloxy)phenyl)propionic acid; D000598:Amino Acids, Cyclic; D027283:Large Neutral Amino Acid-Transporter 1; D011355:Prodrugs; C006504:2-aminobicyclo(2,2,1)heptane-2-carboxylic acid; D014443:Tyrosine; D007660:Ketoprofen; D007930:Leucine