Systemic and Brain Pharmacokinetics of Perforin Inhibitor Prodrugs.
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.
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland , P.O. Box 1627, FI-70211 Kuopio, Finland.
Mikko
M
Gynther
Department of Drug Design and Pharmacology, Faculty of Health & Medical Sciences, University of Copenhagen , Jagtvej 160, 1165 Copenhagen, Denmark.
Darryl S
DS
Pickering
Auckland Cancer Society Research Centre, The University of Auckland , Private Bag 92019, Auckland 1142, New Zealand.
Julie A
JA
Spicer
Auckland Cancer Society Research Centre, The University of Auckland , Private Bag 92019, Auckland 1142, New Zealand.
William A
WA
Denny
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland , P.O. Box 1627, FI-70211 Kuopio, Finland.
Kristiina M
KM
Huttunen
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001692:Biological Transport / Q000502:physiology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D005260:Female; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D054353:Perforin / Q000037:antagonists & inhibitors*; D011247:Pregnancy; D011355:Prodrugs / Q000493:pharmacokinetics*; D014991:Xylazine / Q000494:pharmacology
D011355:Prodrugs; D054353:Perforin; D014991:Xylazine; D007649:Ketamine
brain uptake; perforin inhibitor; pharmacokinetics; prodrug; transporter