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Brain Pharmacokinetics of Two Prolyl Oligopeptidase Inhibitors, JTP‐4819 and KYP‐2047, in the Rat
Author(s) -
Jalkanen Aaro J.,
Hakkarainen Jenni J.,
Lehtonen Marko,
Venäläinen Tetta,
Kääriäinen Tiina M.,
Jarho Elina,
Suhonen Marjukka,
Forsberg Markus M.
Publication year - 2011
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2011.00747.x
Subject(s) - in vivo , pharmacokinetics , pharmacology , blood–brain barrier , extracellular fluid , in vitro , medicine , extracellular , chemistry , biochemistry , biology , central nervous system , microbiology and biotechnology
Prolyl oligopeptidase (PREP) inhibitors are potential drug candidates for the treatment of neurological disorders, but little is known about their ability to cross the blood–brain barrier and to reach the target site. This study characterizes brain pharmacokinetics of two potent PREP inhibitors, JTP‐4819 and KYP‐2047. Firstly, the in vitro permeability ( P app ) of JTP‐4819 and KYP‐2047 through a bovine brain microvessel endothelial cell monolayer was assessed. Then, the in vivo brain/blood ratio was determined for the total brain and plasma concentrations and also for the unbound extracellular drug concentrations after a single dose (50 μmol/kg i.p.). KYP‐2047 had a significantly higher P app than JTP‐4819. In vivo , KYP‐2047 had higher total and unbound brain/blood ratios. KYP‐2047 was equally distributed between the cortex, hippocampus and striatum. In the case of JTP‐4819, the unbound brain extracellular concentrations could not be readily predicted from the unbound blood levels, probably because of its poor membrane penetration properties. KYP‐2047 displayed a better ability to reach the intracellularly located brain PREP, and it inhibited this enzyme more effectively than JTP‐4819 after an equimolar single dose. In conclusion, KYP‐2047 showed better brain penetration characteristics than JTP‐4819 both in vitro and in vivo . KYP‐2047 is a brain‐penetrating, potent and long‐acting PREP inhibitor; thus, it represents a convenient pharmacological tool for assessing the potential of PREP as a drug target.