TY - JOUR T1 - AIT-082, a Cognitive Enhancer, Is Transported into Brain by a Nonsaturable Influx Mechanism and out of Brain by a Saturable Efflux Mechanism JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 813 LP - 821 VL - 293 IS - 3 AU - Eve M. Taylor AU - Rongzi Yan AU - Nils Hauptmann AU - Timothy J. Maher AU - Daniela Djahandideh AU - Alvin J. Glasky Y1 - 2000/06/01 UR - http://jpet.aspetjournals.org/content/293/3/813.abstract N2 - A fundamental feature of any drug designed to treat a disease of the central nervous system is the ability to cross the blood-brain barrier. Passage across the blood-brain barrier of AIT-082, a cognitive enhancer, was investigated in mice. [14C]AIT-082 crossed the blood-brain barrier in young male Swiss-Webster mice with a mean influx constant (Ki) of 0.6 ± 0.2 μl g−1 min−1. Furthermore, [14C]AIT-082 was transported into brain of both young and old male C57BL/6 mice with a Ki of 0.35 ± 0.06 and 0.33 ± 0.02 μl g−1 min−1, respectively. There was no significant effect of age or strain on the movement of [14C]AIT-082 across the blood-brain barrier in mice. When 110- or 650-fold excess unlabeled AIT-082 was included in the injection solution, the Ki was not significantly changed in either Swiss-Webster or C57BL/6 mice. This indicated that [14C]AIT-082 crossed the blood-brain barrier by a nonsaturable mechanism. The passage of AIT-082 into brain extracellular fluid was confirmed with capillary depletion and microdialysis. The efflux of [14C]AIT-082 from brain also was examined. After i.c.v. injection, [14C]AIT-082 levels in brain decreased over time with a t1/2 of 20.0 ± 1.0 min. Excess unlabeled AIT-082 (600-fold) increased thet1/2 to 35.5 ± 3.6 min. Together, these data indicate that AIT-082 moves into brain via a nonsaturable mechanism and is actively transported out of brain. The American Society for Pharmacology and Experimental Therapeutics ER -