Circadian variation of Valproic acid pharmacokinetics in mice

Valproic acid (VPA) is currently one of the most commonly used antiepileptic drugs. This study aims to investigate whether VPA pharmacokinetics varied according to circadian dosing-time. A single dose of VPA (350 mgkg(-1)) was administered by intraperitonally (i.p.) route to a total of 132 mice synchronized for 3 weeks to 12h light (rest span) and 12 h dark (activity span). Four different circadian times (1, 7, 13 and 19 HALO) of drug injection were used (33 mice/circadian time). At each circadian time, blood samples were withdrawn at (0 h) and at 0.083, 0.166, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2 and 3h after VPA injection. Plasma VPA concentrations were determined by an EMIT method. There were no significant differences in T(max) of VPA whatever the circadian-time of injections (T(max)=0.166 h). However, there were relevant differences in C(max) between the four circadian groups (p<0.005), it varied between 386 ± 30.86 mg L(-1) in mice treated at 7 HALO and 824 ± 39.85 mg L(-1) in mice treated at 19 HALO. The AUC(0-∞) was significantly two times higher when VPA was administered at 19 HALO as compared to the injection at 7 HALO. Drug dosing at 7 HALO resulted in highest Cl(T) value: 0.405 ± 0.006 L h(-1)kg(-1), whereas Cl(T) was significantly slower when VPA was administered at 19 HALO (0.157 ± 0.009 L h(-1)kg(-1)) (p<0.0001). The AUC(0-∞) was significantly 2-fold higher when VPA was administered at 19 HALO (2216.65 ± 138.91 mg h(-1)L(-1)) as compared to the injection at 7 HALO (864.09 ± 16.82 mg h(-1)L(-1)) (p<0.0001). Cosinor analysis showed circadian rhythm in different pharmacokinetic parameters. C(max) and AUC(0-∞) have a significant circadian rhythm with an acrophase located at 20.16 HALO ± 0.16 h (the middle of the active span) (p<0.001), whereas Cl(T) and Vd showed a significant circadian rhythm with an acrophase located respectively at 7.86 HALO ± 0.57 h and 6.13 HALO ± 0.07 h (the middle of the rest span) (p<0.001). The large circadian variation of VPA pharmacokinetic processes might be involved in the mechanisms of circadian rhythm in murine toxicity since the optimal tolerance corresponded to the time which induces lowest C(max) and AUC values.