title: Glucose promoiety enables glucose transporter mediated brain uptake of ketoprofen and indomethacin prodrugs in rats.
abstract: The brain uptake of solutes is efficiently governed by the blood-brain barrier (BBB). The BBB expresses a number of carrier-mediated transport mechanisms, and new knowledge of these BBB transporters can be used in the rational targeted delivery of drug molecules for active transport. One attractive approach is to conjugate an endogenous transporter substrate to the active drug molecule to utilize the prodrug approach. In the present study, ketoprofen and indomethacin were conjugated with glucose and the brain uptake mechanism of the prodrugs was determined with the in situ rat brain perfusion technique. Two of the prodrugs were able to significantly inhibit the uptake of glucose transporter (GluT1)-mediated uptake of glucose, thereby demonstrating affinity to the transporter. Furthermore, the prodrugs were able to cross the BBB in a temperature-dependent manner, suggesting that the brain uptake of the prodrugs is carrier-mediated.
authors.affiliation: Department of Pharmaceutical Chemistry, University of Kuopio, P.O. Box 1627, FI-70211 Kuopio, Finland. mikko.gynther@uku.fi
authors.forename: Mikko
authors.initials: M
authors.lastname: Gynther
authors.forename: Jarmo
authors.initials: J
authors.lastname: Ropponen
authors.forename: Krista
authors.initials: K
authors.lastname: Laine
authors.forename: Jukka
authors.initials: J
authors.lastname: Leppänen
authors.forename: Paula
authors.initials: P
authors.lastname: Haapakoski
authors.forename: Lauri
authors.initials: L
authors.lastname: Peura
authors.forename: Tomi
authors.initials: T
authors.lastname: Järvinen
authors.forename: Jarkko
authors.initials: J
authors.lastname: Rautio
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods; D005947:Glucose / Q000737:chemistry* / Q000378:metabolism; D051246:Glucose Transport Proteins, Facilitative / Q000037:antagonists & inhibitors*; D007213:Indomethacin / Q000493:pharmacokinetics*; D007660:Ketoprofen / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats
chemical_list: D051246:Glucose Transport Proteins, Facilitative; D011355:Prodrugs; D007660:Ketoprofen; D005947:Glucose; D007213:Indomethacin