Modeling Drug- and System-related Changes in Body Temperature: Application to Clomethiazole-induced Hypothermia, Long-lasting Tolerance Development, and Circadian Rhythm in Rats.
From: PK/PD Section, DMPK & Bioanalytical Chemistry, Local Discovery Research Area CNS & Pain Control, AstraZeneca R&D Södertälje, Sweden. sandra.visser@astrazeneca.com
The Journal of pharmacology and experimental therapeutics
- Publish Date: Apr 2006
- ISSN: 0022-3565
- Volume: 317
- Issue: 1
- Pages: 209-19
- Medium: Print
- Language: English
- Citation (JAMA): Visser Sandra A G, Sällström Björn, Forsberg Tomas, et al. Modeling Drug- and System-related Changes in Body Temperature: Application to Clomethiazole-induced Hypothermia, Long-lasting Tolerance Development, and Circadian Rhythm in Rats.. J. Pharmacol. Exp. Ther. Apr 2006;317:209-19
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.
Mesh Headings (Keywords): Animals, Body Temperature, Chlormethiazole, Circadian Rhythm, Disease Models, Animal, Drug Tolerance, Hypnotics and Sedatives, Hypothermia, Male, Rats, Rats, Sprague-Dawley
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