title: Modeling drug- and system-related changes in body temperature: application to clomethiazole-induced hypothermia, long-lasting tolerance development, and circadian rhythm in rats.
abstract: 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 micromol kg(-1) and 24-h s.c. continuous infusions of 0, 20, and 40 micromol kg(-1) h(-1) using osmotic pumps. The duration of tolerance was studied by repeated injections of 300 micromol 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 microM. 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.
authors.affiliation: PK/PD Section, DMPK & Bioanalytical Chemistry, Local Discovery Research Area CNS & Pain Control, AstraZeneca R&D Södertälje, Sweden. sandra.visser@astrazeneca.com
authors.forename: Sandra A G
authors.initials: SA
authors.lastname: Visser
authors.forename: Björn
authors.initials: B
authors.lastname: Sällström
authors.forename: Tomas
authors.initials: T
authors.lastname: Forsberg
authors.forename: Lambertus A
authors.initials: LA
authors.lastname: Peletier
authors.forename: Johan
authors.initials: J
authors.lastname: Gabrielsson
mesh_terms: D000818:Animals; D001831:Body Temperature; D002719:Chlormethiazole / Q000493:pharmacokinetics / Q000494:pharmacology*; D002940:Circadian Rhythm; D004195:Disease Models, Animal; D004361:Drug Tolerance; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D007035:Hypothermia / Q000139:chemically induced*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D006993:Hypnotics and Sedatives; D002719:Chlormethiazole