%0 Journal Article %A Sandra A. G. Visser %A Björn Sällström %A Tomas Forsberg %A Lambertus A. Peletier %A Johan Gabrielsson %T Modeling Drug- and System-Related Changes in Body Temperature: Application to Clomethiazole-Induced Hypothermia, Long-Lasting Tolerance Development, and Circadian Rhythm in Rats %D 2006 %R 10.1124/jpet.105.095224 %J Journal of Pharmacology and Experimental Therapeutics %P 209-219 %V 317 %N 1 %X 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 μmol kg–1 and 24-h s.c. continuous infusions of 0, 20, and 40 μmol kg–1 h–1 using osmotic pumps. The duration of tolerance was studied by repeated injections of 300 μmol kg–1 at 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 ± 1 μM. The delay in onset of tolerance was estimated via a series of four transit compartments at 7.6 ± 2 h. The long-lasting tolerance was assumed to be caused by inactivation of a mediator with an estimated turnover time of 46 ± 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. The American Society for Pharmacology and Experimental Therapeutics %U https://jpet.aspetjournals.org/content/jpet/317/1/209.full.pdf