title: Amino Acid Promoieties Alter Valproic Acid Pharmacokinetics and Enable Extended Brain Exposure.
abstract: 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.
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, P.O. Box 1627, 70211, Kuopio, Finland. mikko.gynther@uef.fi.
authors.forename: Mikko
authors.identifier: http://orcid.org/0000-0002-1403-299X
authors.initials: M
authors.lastname: Gynther
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, P.O. Box 1627, 70211, Kuopio, Finland.
authors.forename: Lauri
authors.initials: L
authors.lastname: Peura
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, P.O. Box 1627, 70211, Kuopio, Finland.
authors.forename: Monika
authors.initials: M
authors.lastname: Vernerová
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, P.O. Box 1627, 70211, Kuopio, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Leppänen
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, P.O. Box 1627, 70211, Kuopio, Finland.
authors.forename: Jussi
authors.initials: J
authors.lastname: Kärkkäinen
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, P.O. Box 1627, 70211, Kuopio, Finland.
authors.forename: Marko
authors.initials: M
authors.lastname: Lehtonen
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, P.O. Box 1627, 70211, Kuopio, Finland.
authors.forename: Jarkko
authors.initials: J
authors.lastname: Rautio
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, P.O. Box 1627, 70211, Kuopio, Finland.
authors.forename: Kristiina M
authors.initials: KM
authors.lastname: Huttunen
mesh_terms: D000596:Amino Acids / Q000008:administration & dosage / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D014635:Valproic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D000596:Amino Acids; D011355:Prodrugs; D014635:Valproic Acid
keywords: Brain uptake; L-Type amino acid transporter 1 (LAT1); Pharmacokinetics; Prodrug; Valproic acid