Figure 6
Effect of the repeated administration of PRE-084 (PRE) on capsaicin-sensitized mice and on nonsensitized animals, and the in vitro metabolic stability of PRE and pregabalin (PGB) in mouse liver microsomes.
(A) Mice were subcutaneously (s.c.) injected with PRE 32 mg/kg or its solvent (saline) once a day (q.d.) for 7 consecutive days, and were tested 24 h after the last s.c. administration. The results represent latency to paw withdrawal in response to stimulation with a punctate mechanical stimulus (0.5 g force) 15 min after the intraplantar (i.pl.) administration of capsaicin (0.125 μg) or its vehicle (DMSO 1%). Animals were always stimulated in the injected paw. Each bar and vertical line represents the mean ± SEM of the values obtained in 8–10 animals. Statistically significant differences between the values from mice treated i.pl. with capsaicin and repeatedly treated with PRE or its solvent: **p < 0.01. Statistically significant differences between mice repeatedly treated with PRE and treated i.pl. with capsaicin or its vehicle: ##p < 0.01. There were no significant differences between mice treated i.pl. with capsaicin vehicle and repeatedly treated with PRE or its solvent (two-way ANOVA followed by Bonferroni test). (B, C and D) Indicators of the in vitro metabolic stability of PRE-084 and PGB: (A) percent remaining drug after incubation for 1 h, (B) intrinsic clearance of the drug (Cl int), and (C) metabolic half-life (t1/2). The concentration of compounds was determined by ultra-high performance liquid chromatography and tandem mass spectrometry after incubation in mouse liver microsomes. Each bar and vertical line represents the mean ± SEM of values obtained in 3 samples. Statistically significant differences between the values obtained after incubation with PRE or PGB in mouse liver microsomes: **p < 0.01 (Student’s t test).
