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Systemic and Brain Pharmacokinetics of Perforin Inhibitor Prodrugs.
Gynther, Mikko; Pickering, Darryl S; Spicer, Julie A; Denny, William A; Huttunen, Kristiina M.
Afiliación
  • Gynther M; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland , P.O. Box 1627, FI-70211 Kuopio, Finland.
  • Pickering DS; Department of Drug Design and Pharmacology, Faculty of Health & Medical Sciences, University of Copenhagen , Jagtvej 160, 1165 Copenhagen, Denmark.
  • Spicer JA; Auckland Cancer Society Research Centre, The University of Auckland , Private Bag 92019, Auckland 1142, New Zealand.
  • Denny WA; Auckland Cancer Society Research Centre, The University of Auckland , Private Bag 92019, Auckland 1142, New Zealand.
  • Huttunen KM; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland , P.O. Box 1627, FI-70211 Kuopio, Finland.
Mol Pharm ; 13(7): 2484-91, 2016 07 05.
Article en En | MEDLINE | ID: mdl-27266990
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 the in vivo and brain pharmacokinetics of two perforin inhibitors and their LAT1-utilizing prodrugs 1 and 2. In addition, the brain uptake mechanism and entry into primary mouse cortical neurons and astrocytes were evaluated. After 23 µmol/kg i.p. bolus injection, the prodrugs' unbound area under the concentration curve in brain was 0.3 nmol/g × min, whereas the parent drugs could not reach the brain. The unbound brain concentrations of the prodrugs after 100 µM in situ mouse brain perfusion were 521.4 ± 46.9 and 126.9 ± 19.9 pmol/g for prodrugs 1 and 2, respectively. The combination of competing transporter substrates for LAT1, l-tryptophan, and for organic anion transporting polypeptides, probenecid, decreased the brain concentrations to 352.4 ± 44.5 and 70.9 ± 7.0 pmol/g, respectively. In addition, in vitro uptake studies showed that at 100 µM prodrug 1 had 3.4-fold and 4.5-fold higher uptake rate into neurons and astrocytes, respectively, compared to its parent drug. Thus, the prodrugs enhance significantly the therapeutic potential of the parent drugs for the treatment of disorders of central nervous system in which neuroinflammation is involved.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Encéfalo / Profármacos / Perforina Límite: Animals / Pregnancy Idioma: En Revista: Mol Pharm Asunto de la revista: BIOLOGIA MOLECULAR / FARMACIA / FARMACOLOGIA Año: 2016 Tipo del documento: Article País de afiliación: Finlandia

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Encéfalo / Profármacos / Perforina Límite: Animals / Pregnancy Idioma: En Revista: Mol Pharm Asunto de la revista: BIOLOGIA MOLECULAR / FARMACIA / FARMACOLOGIA Año: 2016 Tipo del documento: Article País de afiliación: Finlandia