Glucose Promoiety Enables Glucose Transporter Mediated Brain Uptake of Ketoprofen and Indomethacin Prodrugs in Rats

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• 作者：Mikko Gynther ; Jarmo Ropponen ; Krista Laine ; Jukka Leppnen ; Paula Haapakoski ; Lauri Peura ; Tomi Jrvinen ; Jarkko Rautio
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：May 28, 2009
• 年：2009
• 卷：52
• 期：10
• 页码：3348-3353
• 全文大小：127K
• 年卷期：v.52,no.10(May 28, 2009)
• ISSN：1520-4804

文摘

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.