文摘
This study is designed to investigate whether the pharmacokinetics of the antituberculous agent isoniazid (INH) varied according to the circadian dosing-time.MethodsA total of 168 male mice aged 10 weeks and synchronized for 3 weeks to 12 h light and 12 h dark were used. A single INH (100 mg/kg) dose was administered by intraperitonal (i.p.) route at either of the four different circadian stages (1, 7, 13 and 19 h after light onset, HALO). At each circadian stage, blood samples were withdrawn at 0, 0.1, 0.2, 0.4, 1, 1.3, 2, 2.5, 4, 5, 6.3, 8, 24 and 48 h following drug injection. The pharmacokinetics parameters (AUC0-∞, Ke, Cmax, T 1/2, ClT and Vd) were calculated for each circadian-time.ResultsThere were relevant differences in Cmax between the four circadian groups (p < 0.005), maximum and minimum Cmax were obtained when INH was injected at 1 HALO (490 mg L−1) and at 7 HALO (270 mg L−1) respectively. AUC0-∞ also varied significantly according to the circadian-time of injection (2093 mg L−1 h−1 at 1 HALO vs 759 mg L−1 h−1 at 7 HALO) (p < 0.05). The highest and lowest mean values of plasma clearance (Cl) were observed at 7 HALO (0.22 L h−1 kg−1) and 1 HALO (0.13 L h−1 kg−1) respectively (p < 0.05). The Cosinor analysis showed a circadian rhythm in different pharmacokinetic parameters. Cmax and AUC0-∞ have a significant circadian rhythm with an acrophase located at 2.64 HALO ± 0.21 h (the beginning of the rest span) (p < 0.001), whereas ClT and Vd showed a significant circadian rhythm with an acrophase located respectively at 7.4 HALO and at 8.66 HALO (the second half of the rest span) (p < 0.001).ConclusionPlasma INH chronopharmacokinetics might be involved in the mechanism of circadian variation of toxicity since the time of optimal tolerance to INH corresponds to that of the lowest Cmax and AUC0-∞ and the highest ClT occured when this drug injected in the second half of light-rest phase (7 HALO).
