Modeling Drug- and System-Related Changes in Body Temperature: Application to Clomethiazole-Induced Hypothermia, Long-Lasting Tolerance Development, and Circadian Rhythm in Rats
- PK/PD Section, DMPK & Bioanalytical Chemistry, Local Discovery Research Area CNS & Pain Control, AstraZeneca R&D Södertälje, Södertälje, Sweden (S.A.G.V.); General Pharmacology, Local Discovery Research Area CNS & Pain Control, AstraZeneca R&D Södertälje, Sweden (T.F.); Mathematical Institute, Leiden University, Leiden, and Centrum voor Wiskunde en Informatica, Amsterdam, The Netherlands (L.A.P.); and DMPK & Bioanalytical Chemistry, AstraZeneca R&D Mölndal, Mölndal, Sweden (J.G.)
- Address correspondence to:
Dr. Sandra A. G. Visser, PK/PD Section, DMPK&BAC, AstraZeneca R&D Södertälje, SE-151 85 Södertälje, Sweden. E-mail: sandra.visser{at}astrazeneca.com
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 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.
Footnotes
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Preliminary results were presented at the annual meeting of the Population Approach Group Europe (PAGE), June 17–18, 2004, Uppsala, Sweden [Visser SAG, Sällström B, Forsberg T, Peletier LA, and Gabrielsson J (2004) Modeling of drug- and system-related changes in body temperature: application to drug-induced hypothermia, long-lasting tolerance development and circadian rhythm in body temperature [PAGE 13 (2004) Abstract 512. www.pagemeeting.org/?abstract=512].
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doi:10.1124/jpet.105.095224.
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ABBREVIATIONS: CMZ, clomethiazole; PK/PD, pharmacokinetic-pharmacodynamic.
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- Received September 20, 2005.
- Accepted December 1, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
