Large neutral amino acid transporter enables brain drug delivery via prodrugs

Mikko Gynther; Krista Laine; Jarmo Ropponen; Jukka Leppänen; Anne Mannila; Tapio Nevalainen; Jouko Savolainen; Tomi Järvinen; Jarkko Rautio

doi:10.1021/jm701175d

Large neutral amino acid transporter enables brain drug delivery via prodrugs

Mikko Gynther^*, Krista Laine, Jarmo Ropponen, Jukka Leppänen, Anne Mannila, Tapio Nevalainen, Jouko Savolainen, Tomi Järvinen, Jarkko Rautio

^*Corresponding author for this work

Not published at VTT

Research output: Contribution to journal › Article › Scientific › peer-review

146 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	932-936
Journal	Journal of Medicinal Chemistry
Volume	51
Issue number	4
DOIs	https://doi.org/10.1021/jm701175d
Publication status	Published - 28 Feb 2008
MoE publication type	A1 Journal article-refereed

Access to Document

10.1021/jm701175d

Cite this

@article{cc579666a8d14dbca3902707dd12bade,

title = "Large neutral amino acid transporter enables brain drug delivery via prodrugs",

abstract = "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.",

author = "Mikko Gynther and Krista Laine and Jarmo Ropponen and Jukka Lepp{\"a}nen and Anne Mannila and Tapio Nevalainen and Jouko Savolainen and Tomi J{\"a}rvinen and Jarkko Rautio",

year = "2008",

month = feb,

day = "28",

doi = "10.1021/jm701175d",

language = "English",

volume = "51",

pages = "932--936",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "4",

}

TY - JOUR

T1 - Large neutral amino acid transporter enables brain drug delivery via prodrugs

AU - Gynther, Mikko

AU - Laine, Krista

AU - Ropponen, Jarmo

AU - Leppänen, Jukka

AU - Mannila, Anne

AU - Nevalainen, Tapio

AU - Savolainen, Jouko

AU - Järvinen, Tomi

AU - Rautio, Jarkko

PY - 2008/2/28

Y1 - 2008/2/28

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=39749166269&partnerID=8YFLogxK

U2 - 10.1021/jm701175d

DO - 10.1021/jm701175d

M3 - Article

C2 - 18217702

AN - SCOPUS:39749166269

SN - 0022-2623

VL - 51

SP - 932

EP - 936

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 4

ER -

Large neutral amino acid transporter enables brain drug delivery via prodrugs

Abstract

Access to Document

Other files and links

Fingerprint

Cite this