DOSING TIME DEPENDENT EFFICACIES OF VARIOUS ANESTHETICS IN MICE

 

Yuki Sato¹², Eiji Kobahashi², Tasuku Wainai¹, Takanori Murayama¹, and Norimasa Seo¹

 

¹Department of Anesthesiology, and ²Center for Molecular Medicine, Jichi Medical School

 

Purpose: Chronotherapy has recently become an advanced field because the efficacy of many drugs varies depending on the time of administration.     In this study, we examined whether intravenous anesthetic drugs have dosing time dependent efficacies.

Method: Male C57BL/6 mice, which showed clear circadian rhythms of water-intake under the strict control of 12-hour lighting, were used. Two-hundred mg/kg ketamine, 50 mg/kg pentobarbital, 100 mg/kg propofol, 50 mg/kg midazolam, and 25 mg/kg diazepam were injected intraperitoneally at 3 and 15 hours after light on (HALO), respectively. Anesthetic effectiveness was evaluated by the duration of loss of righting reflex (LORR).  The activity levels of cytocromes P450 (CYPs) isoenzymes in liver at 3 and 15 HALO were also measured. 

Result: Ketamine, pentobarbital, and propofol were significantly more effective in inducing anesthesia at 15 HALO than at 3 HALO, while midazolam and diazepam worked longer at 3 HALO. Although the hepatic flow is generally considered to increase in active phase, the activities of CYPs in liver showed no significant difference between two different dosing times.

Conclusion: We demonstrated that intravenous anesthetics indicated diverse dosing time dependent efficacy in consistency with circadian rhythms of mice. Furthermore, our findings suggested that these different anesthetic efficacies could be explained by the differences in sensitivity of central nerves system rather than pharmacokinetics.