The aim of the present investigation was to develop a pharmacokinetic-pharmacodynamic model for the characterization of clomethiazole (CMZ)-induced hypothermia and the rapid development of long-lasting tolerance in rats while taking into account circadian rhythm in baseline and the influence of handling. CMZ-induced hypothermia and tolerance was measured using body temperature telemetry in male Sprague-Dawley rats, which were given s.c. bolus injections of 0, 15, 150, 300, and 600 mol kg Ϫ1 and 24-h s.c. continuous infusions of 0, 20, and 40 mol kg Ϫ1 h Ϫ1 using osmotic pumps. The duration of tolerance was studied by repeated injections of 300 mol kg
Ϫ1at 3-to 32-day intervals. Plasma exposure to CMZ was obtained in satellite groups of catheterized rats. Fitted population concentration-time profiles served as input for the pharmacodynamic analysis. The asymmetric circadian rhythm in baseline body temperature was successfully described by a novel negative feedback model incorporating external light-dark conditions. An empirical function characterized the transient increase in temperature upon handling of the animal. A feedback model for temperature regulation and tolerance development allowed estimation of CMZ potency at 30 Ϯ 1 M. The delay in onset of tolerance was estimated via a series of four transit compartments at 7.6 Ϯ 2 h. The long-lasting tolerance was assumed to be caused by inactivation of a mediator with an estimated turnover time of 46 Ϯ 3 days. This multicomponent turnover model was able to quantify the CMZ-induced hypothermia, circadian rhythm in baseline, and rapid onset of a long-lasting tolerance to CMZ in rats.Clomethiazole (CMZ) has sedative, hypnotic, anticonvulsive, and neuroprotective properties and has been used clinically in elderly patients as a useful sedative/hypnotic for 40 years (Green, 1998). In a recent investigation, we showed that CMZ is able to induce hypothermia in rats and that even a single injection of CMZ rapidly induces complete tolerance lasting for more than 10 days, with a 50% return of effect after a month . This observation of tolerance partly explained why conflicting reports exist regarding the ability of CMZ to induce hypothermia and the relationship between hypothermia and neuroprotective properties in vivo (Cross et al., 1991;Green, 1998;Chaulk et al., 2003). For CMZ, it was observed that the tolerance is induced directly by the drug, rather than via a decrease in body temperature, because hypothermic tolerance to CMZ did not affect hypothermic responses to other drugs and could not be attenuated . Moreover, the tolerance appeared to last for more than 15 days, which suggests that CMZ downregulated a necessary but so far unknown mediator, which by itself has a slow turnover. In the present investigation the objective was to quantify the CMZ-induced hypothermia and the rapid onset of long-lasting tolerance by developing a pharmacokinetic-pharmacodynamic (PK/PD) model. Article, publication date, and citation information can be found at