Circadian variation of isoniazid pharmacokinetics in mice

Abstract

Introduction: This study is designed to investigate whether the pharmacokinetics of the antituberculous agent isoniazid (INH) varied according to the circadian dosing-time.

Methods: A total of 168 male mice aged 10 weeks and synchronized for 3 weeks to 12h light and 12h dark were used. A single INH (100mg/kg) dose was administered by intraperitonal (i.p.) route at either of the four different circadian stages (1, 7, 13 and 19h 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 At each circadian stage, blood samples were withdrawn at 0, 0.1, 0.2, 0.4, 1, 1.3, 2, 2.5, 4, 5, 6.3, 8, 24 and 48h following drug injection. The pharmacokinetics parameters (AUC_0-∞, Ke, C_max, T 1/2, Cl_T and V_d) were calculated for each circadian-time.

Results: There were relevant differences in C_max between the four circadian groups (p<0.005), maximum and minimum C_max were obtained when INH was injected at 1 HALO (490mgL^-1) and at 7 HALO (270mgL^-1) respectively. AUC_0-∞ also varied significantly according to the circadian-time of injection (2093mgL^-1h^-1 at 1 HALO vs 759mgL^-1h^-1 at 7 HALO) (p<0.05). The highest and lowest mean values of plasma clearance (Cl) were observed at 7 HALO (0.22Lh^-1kg^-1) and 1 HALO (0.13Lh^-1kg^-1) respectively (p<0.05). The Cosinor analysis showed a circadian rhythm in different pharmacokinetic parameters. C_max and AUC_0-∞ have a significant circadian rhythm with an acrophase located at 2.64 HALO±0.21h (the beginning of the rest span) (p<0.001), whereas Cl_T and V_d 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).

Conclusion: Plasma 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 C_max and AUC_0-∞ and the highest Cl_T occured when this drug injected in the second half of light-rest phase (7 HALO).

Keywords: Blood samples; Circadian rhythm; Cosinor; Intraperitoneal route; Isoniazid; Mice; Pharmacokinetic.