Pharmacokinetic studies in the male CD rat, performed at 1 mg/kg, iv and 3 mg/kg, po, demonstrate an excellent pharmacokinetic profile for a hypnotic agent featuring moderate clearance in plasma (Cl p =24 mL/min/kg), short half-life of (<0.6 h) and a low volume of distribution (V ss =1.1 l/kg), coupled with excellent oral bioavailability (F=85%) and good exposure in plasma (C max =333 ng/mL). A brain to blood ratio (B/B) of 0.1:1 is observed 1 h after iv administration, a value in line with the expected partition between the two compartments based on the lower tissue binding observed in vitro in brain tissues (fraction unbound/brain=5.28%) with respect to plasma proteins (fraction unbound/plasma=1.34%). SB-649868, administered orally 3 h before OX-A injection at doses of 1, 3 and 10 mg/kg, causes a dose-dependent reduction of OX-A induced grooming as measured by total time spent grooming and number of grooming bouts ( p <0.01 at 3 a nd 10 mg/kg po) . From dissociation kinetic studies using [ 3 H]ACT-078573, the calculated long half-life, (t 1/2 ) supports the non-surmountability profile of SB-649868 (t 1/2 =35.91 min) at OX 1 orexin receptor. The long or moderately long t 1/2 < /sub> values for SB-649868 at OX 2 orexin receptor (t 1/2 =8.09 min).
