Session Speaker

An Effective and Selective Brain Drug Delivery via Amino Acid Prodrugs
Rautio Jarkko , Gynther Mikko, Laine Krista, Ropponen Jarmo, Forsberg Markus, Jalkanen Aaro, Leppänen Jukka
Finland

Our studies show for the very first time that a drug-substrate conjugate is able to transport drugs into the brain via large neutral amino acid transporter (LAT1) offering a feasible drug delivery method for CNS drugs.

Of several various amino acid prodrugs1 which were designed and synthesized, tyrosine and lysine derivatives showed affinity for LAT1 since they were able to significantly (79-98.5%) decrease the brain uptake of [14C]-L-leucine, a known LAT1 substrate, in competition studies carried out using an in situ rat brain perfusion technique. More importantly, these prodrugs showed concentration-dependent brain uptake after in situ experiments which was significantly inhibited by a specific LAT1 inhibitor, BCH, thus demonstrating carried-mediated uptake. in vivo Single bolus experiments (10 and 120 min experiments) indicated very rapid and high, respectively, brain uptake of prodrugs which were further confirmed in extensive microdialysis studies. Moreover, the localization of the released parent drug from amino acid prodrugs was indicated to be intracellular within the brain tissue (1.6-fold increase compared to parent drug), while plasma concentration remained 4.6-fold lower than those after parent drug dose. Therefore, our prodrugs demonstrate very effective parent drug targeting to the site of its action - brain and its intracellular compartments. This strategy may offer a significant means for rapid and selective shuttling of various CNS drugs into brain.

Part of the research was published in Journal of Medicinal Chemistry in 2008 (J Med Chem 51: 932-936, 2008) and in The AAPS Journal (The AAPS Journal (Theme Issue: Current advances in CNS delivery of therapeutic molecules) 10(1): 92-102, 2008). Moreover, third manuscript is submitted.

Similarly, a part of the study was orally represented by invitation on UCB Research Day (Overcoming the blood-brain barrier: Dreams & facts), November 3rd, 2008, as well as at the AAPS meeting (roundtable: “Prodrug approaches for organ specific targeted therapy”) on Nov 2008.

NONE of the publications or oral presentations has included all the data meant to be included in this oral presentation.

References:

1. Rautio, J.; Kumpulainen, H.; Heimbach, T.; Oliyai, R.; Oh, D.; Jarvinen, T.; Savolainen, J., Prodrugs: design and clinical applications. Nat Rev Drug Discov 2008, 7, (3), 255-70.