Amino Acid Promoieties Alter Valproic Acid Pharmacokinetics and Enable Extended Brain Exposure
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Valproic acid (VPA) has been used to treat epileptic seizures for decades, but it may also possess therapeutic potential in other nervous system diseases. However, VPA is extensively bound to plasma proteins, asymmetrically transported across the blood–brain barrier and metabolized to toxic species in the liver, which all contribute to its severe off-target adverse effects and possible drug–drug interactions. In this study, we evaluated seven amino acid prodrugs of VPA that were targeted to utilize l-type amino acid transporter 1 (LAT1), if they could alter the brain uptake mechanism and systemic pharmacokinetics of VPA. All prodrugs had affinity for LAT1 studied as competitive inhibition of [14C]-l-leucine in human breast cancer (MCF-7) cell line. However, since the ester prodrugs were unstable they were not studied further, instead the corresponding amide prodrugs were used to evaluate their systemic pharmacokinetics in rats and the uptake mechanism via LAT1 into the rat brain. All amide prodrugs were bound to a lesser extent to plasma proteins than VPA and this being independent of the prodrug concentration. Amide prodrugs were also delivered into the brain after intravenous bolus injection. One of the prodrug showed greater brain uptake and high selectivity for LAT1 and it was able to release VPA slowly within the brain. Therefore, it was concluded that the VPA brain concentrations can be stabilized as well as the problematic pharmacokinetic profile can be altered by a LAT1-selective prodrug.
KeywordsBrain uptake Pharmacokinetics Prodrug l-Type amino acid transporter 1 (LAT1) Valproic acid
3-Dimensional quantitative structure–activity relationship
γ-Amino butyric acid
High-performance liquid chromatography
l-type amino acid transporter 1
Human breast cancer cell line
Monocarboxylic acid transporter 1
Subcellular fraction (centrifuged at 9000×g)
The work was financially supported by funding of the Academy of Finland , University of Eastern Finland (Postdoctoral program), Päivikki and Sakari Sohlberg’s Foundation, Emil Aaltonen Foundation and Orion Research Foundation. The authors would like to thank Tiina Koivunen for skillful technical assistant with the syntheses, Helly Rissanen for invaluable technical assistance with in vitro bioconversion studies, M.Sc. Johanna Huttunen for performing the in vitro LAT1 affinity studies and Dr. Veli-Pekka Ranta for helpful discussions regarding the pharmacokinetic data analysis as well as Dr. Ewen MacDonald for reviewing the language of the study.
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