Modeling Drug- and System-Related Changes in Body Temperature: Application to Clomethiazole-lnduced Hypothermia,Long-Lasting Tolerance Development,and Circadian Rhythm in Rats

摘要

The aim of the present investigation was to develop a pharma-cokinetic-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 mu mol kg~(-1) and 24-h s.c.continuous infusions of 0,20,and 40 mu mol kg~(-1) h~(-1) using osmotic pumps.The duration of tolerance was studied by repeated injections of 300 mu mol 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 pharmaco-dynamic 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 mu M.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.