Gynther Mikko, Laine Krista, Ropponen Jarmo, Leppänen Jukka, Mannila Anne, Nevalainen Tapio, Savolainen Jouko, Järvinen Tomi, Rautio Jarkko
Department of Pharmaceutical Chemistry, University of Kuopio, PO Box 1627, FI-70211 Kuopio, Finland.
J Med Chem. 2008 Feb 28;51(4):932-6. doi: 10.1021/jm701175d. Epub 2008 Jan 25.
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.
血脑屏障有效地控制药物分子进入大脑。我们描述了一种可行的方法，通过将一种模型化合物与L-酪氨酸偶联，实现载体介导的药物通过特异性大中性氨基酸转运体（LAT1）进入大鼠大脑。选择一种不是LAT1底物的亲水性药物酮洛芬作为模型化合物。采用大鼠原位脑灌注技术确定了前药脑摄取的机制和动力学。发现前药的脑摄取具有浓度依赖性。此外，一种特异性LAT1抑制剂显著降低了前药的脑摄取。因此，我们的结果首次揭示了药物-底物偶联物能够通过LAT1将药物转运到大脑中。
