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ANESTHETIC PHARMACOLOGY

The Dosing-Time Dependent Effects of Intravenous Hypnotics in Mice

Yuki Sato, MD, PhD^*, Norimasa Seo, MD, PhD^*, and Eiji Kobahashi, MD, PhD

*Department of Anesthesiology and Division of Organ Replacement Research, Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan

Address correspondence and reprint requests to Eiji Kobayashi, MD, PhD, Division of Organ Replacement Research, Center for Molecular Medicine, Jichi Medical School, 3311–1, Yakushiji, Minamikawachi, Kawachi, Tochigi 329–0498, Japan. Address e-mail to eijikoba{at}jichi.ac.jp.

Chronobiology, which focuses on the biological rhythms that occur in the organization of living organisms, has been studied for several decades. Chronopharmacology, however, has received little attention until recently. We examined the hypnotic duration of intraperitoneally administered ketamine, pentobarbital, propofol, midazolam, and ethanol, to test whether they have obvious dosing-time dependent effects. Male C57BL/6 mice, which showed clear circadian rhythms of water-intake under a strict 12-h lighting cycle, were used. All tested drugs had significantly longer episodes of loss of righting reflex when administered at 22:00 (early active phase) than at 10:00 (early inactive phase). This dosing-time dependent hypnotic duration did not depend on the contents and activities of cytochrome P450 enzymes in the liver. These findings might be of clinical benefit in deciding the administration time and doses of anesthetics.