Systemic and Brain Pharmacokinetics of Perforin Inhibitor Prodrugs

• DOI: 10.1021/acs.molpharmaceut.6b00217
• Publication Date: 2016-06-06T21:46:11Z
• Authors: Mikko Gynther; Darryl S. Pickering; Julie A. Spicer; William A. Denny; Kristiina M. Hutt...
• Keywords: Male; Neurons; Xylazine; 0303 health sciences; Perforin; Brain; Biological Transport; Mass Spectrometry; 3. Good health; Mice; 03 medical and health sciences; Blood-Brain Barrier; Pregnancy; Astrocytes; Animals; Female; Ketamine; Prodrugs; Cells, Cultured; Chromatography, High Pressure Liquid; Chromatography, Liquid

We have recently reported that by converting a perforin inhibitor into an l-type amino acid transporter 1 (LAT1)-utilizing prodrug its cellular uptake can be greatly increased. The aim of the present study was to determine in vivo and brain pharmacokinetics two inhibitors their LAT1-utilizing prodrugs 2. In addition, mechanism entry primary mouse cortical neurons astrocytes were evaluated. After 23 μmol/kg i.p. bolus injection, prodrugs' unbound area under concentration curve 0.3 nmol/g × min, whereas parent drugs could not reach brain. concentrations after 100 μM situ perfusion 521.4 ± 46.9 126.9 19.9 pmol/g for 2, respectively. combination competing substrates LAT1, l-tryptophan, organic anion transporting polypeptides, probenecid, decreased 352.4 44.5 70.9 7.0 pmol/g, vitro studies showed at had 3.4-fold 4.5-fold higher rate astrocytes, respectively, compared drug. Thus, enhance significantly therapeutic potential treatment disorders central nervous system which neuroinflammation is involved.