Figure 4

Oral bioavailability, brain uptake, safety and metabolic stability of 069A. Compound bioavailability (A and B) was determined by administration of 069A (2.5 mg/kg) by oral gavage to C57Bl/6 mice, processing of blood and brain at different times after administration, and measuring compound levels in plasma and brain homogenate extracts by HPLC as described in Methods. Compound 069A rapidly appears in plasma (A) and brain (B) within 5 min, and then slowly declines to basal levels by 60 min. Data are the mean ± SEM from 5 mice at each time point. Lack of idiopathic tissue injury (C) after chronic administration of compound was assessed by treating C57Bl/6 mice (5 mice per group) with either vehicle (Veh) or 069A (Cmpd; 2.5 mg/kg) by oral gavage once daily for two weeks. Histological liver injury was determined by a scoring system as described in Methods. There is no significant liver toxicity after chronic two-week administration of compound compared to vehicle, the same dose and paradigm used in efficacy testing. To screen for potential metabolic instability (D), compound 069A, the clinical CNS drug Minaprine, or the drug Minozac were incubated with human liver microsomes, and the amount of compound remaining was analyzed by HPLC as described in Methods. Significantly different from time 0 (**p < 0.01; ***p < 0.001).