Vol. 293, Issue 3, 813-821, June 2000

AIT-082, a Cognitive Enhancer, Is Transported into Brain by a Nonsaturable Influx Mechanism and out of Brain by a Saturable Efflux Mechanism¹

Eve M. Taylor, Rongzi Yan, Nils Hauptmann, Timothy J. Maher², Daniela Djahandideh and Alvin J. Glasky

NeoTherapeutics Inc., Irvine, California

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 (K_i) of 0.6 ± 0.2 µl g¹ min¹. Furthermore, [¹⁴C]AIT-082 was transported into brain of both young and old male C57BL/6 mice with a K_i of 0.35 ± 0.06 and 0.33 ± 0.02 µl g¹ min¹, 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 K_i 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 t_1/2 of 20.0 ± 1.0 min. Excess unlabeled AIT-082 (600-fold) increased the t_1/2 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.