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Mechanistic Study o...
Mechanistic Study on the Use of the L-Type Amino Acid Transporter 1 for Brain Intracellular Delivery of Ketoprofen via Prodrug : A Novel Approach Supporting the Development of Prodrugs for Intracellular Targets
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- Puris, Elena (författare)
- Univ Eastern Finland, Sch Pharm, POB 1627, FI-70211 Kuopio, Finland
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- Gynther, Mikko (författare)
- Univ Eastern Finland, Sch Pharm, POB 1627, FI-70211 Kuopio, Finland
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- de Lange, Elizabeth C. M. (författare)
- Leiden Univ, Leiden Acad Ctr Drug Res, Div Syst Biomed & Pharmacol, Predict Pharmacol Grp, NL-2311 EZ Leiden, Netherlands
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- Auriola, Seppo (författare)
- Univ Eastern Finland, Sch Pharm, POB 1627, FI-70211 Kuopio, Finland
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- Hammarlund-Udenaes, Margareta (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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- Huttunen, Kristiina M. (författare)
- Univ Eastern Finland, Sch Pharm, POB 1627, FI-70211 Kuopio, Finland
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- Loryan, Irena, 1977- (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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(creator_code:org_t)
- 2019-06-10
- 2019
- Engelska.
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 16:7, s. 3261-3274
- Relaterad länk:
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https://scholarlypub...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- L-Type amino acid transporter 1 (LAT1), selectively expressed at the blood-brain barrier (BBB) and brain parenchymal cells, mediates brain delivery of drugs and prodrugs such as L-dopa and gabapentin. Although knowledge about BBB transport of LAT1-utilizing prodrugs is available, there is a lack of quantitative information about brain intracellular delivery and influence of prodrugs on the transporter's physiological state. We studied the LAT1-mediated intrabrain distribution of a recently developed prodrug of the cyclooxygenase inhibitor ketoprofen as well as its impact on transporter protein expression and function (i.e., amino acid exchange) using brain slice method in mice and rats. The intrabrain distribution of the prodrug was 16 times higher than that of ketoprofen. LAT1 involvement in brain cellular barrier uptake of the prodrug was confirmed, reflected by a higher unbound brain intracellular compared to brain extracellular fluid concentration. The prodrug did not alter LAT1 protein expression and amino acid exchange. Integration of derived parameters with previously performed in vivo pharmacokinetic study using the Combinatory Mapping Approach allowed to estimate the brain extra- and intracellular levels of unbound ketoprofen, prodrug, and released parent drug. The overall efficiency of plasma to brain intracellular delivery of prodrug-released ketoprofen was 11 times higher than after ketoprofen dosing. In summary, this study provides quantitative information supporting the use of the LAT1-mediated prodrug approach for enhanced brain delivery of drugs with intracellular targets.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Nyckelord
- pharmacokinetics
- transporter
- LAT1
- prodrug
- intrabrain distribution
- brain slice
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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