Development of a mechanism-based pharmacokinetic/pharmacodynamic model to characterize the thermoregulatory effects of serotonergic drugs in mice.
- Author:
Xi-Ling JIANG
1
;
Hong-Wu SHEN
2
;
Donald E MAGER
2
;
Stephan SCHMIDT
3
;
Ai-Ming YU
4
Author Information
1. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214-8033, USA; Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, University of Florida, Orlando, FL 32827, USA.
2. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214-8033, USA.
3. Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, University of Florida, Orlando, FL 32827, USA.
4. Department of Biochemistry & Molecular Medicine, UC Davis School of Medicine, 2700 Stockton Boulevard, Sacramento, CA 95817, USA.
- Publication Type:Journal Article
- Keywords:
Indolealkylamine;
Monoamine oxidase-A inhibitor;
PK/PD model;
Serotonin;
Stress;
Thermoregulation
- From:
Acta Pharmaceutica Sinica B
2016;6(5):492-503
- CountryChina
- Language:English
-
Abstract:
We have shown recently that concurrent harmaline, a monoamine oxidase-A inhibitor (MAOI), potentiates serotonin (5-HT) receptor agonist 5-methoxy--dimethyltryptamine (5-MeO-DMT)-induced hyperthermia. The objective of this study was to develop an integrated pharmacokinetic/pharmacodynamic (PK/PD) model to characterize and predict the thermoregulatory effects of such serotonergic drugs in mice. Physiological thermoregulation was described by a mechanism-based indirect-response model with adaptive feedback control. Harmaline-induced hypothermia and 5-MeO-DMT-elicited hyperthermia were attributable to the loss of heat through the activation of 5-HTreceptor and thermogenesisthe stimulation of 5-HTreceptor, respectively. Thus serotonergic 5-MeO-DMT-induced hyperthermia was readily distinguished from handling/injection stress-provoked hyperthermic effects. This PK/PD model was able to simultaneously describe all experimental data including the impact of drug-metabolizing enzyme status on 5-MeO-DMT and harmaline PK properties, and drug- and stress-induced simple hypo/hyperthermic and complex biphasic effects. Furthermore, the modeling results revealed a 4-fold decrease of apparent SCvalue (1.88-0.496 µmol/L) for 5-MeO-DMT when harmaline was co-administered, providing a quantitative assessment for the impact of concurrent MAOI harmaline on 5-MeO-DMT-induced hyperthermia. In addition, the hyperpyrexia caused by toxic dose combinations of harmaline and 5-MeO-DMT were linked to the increased systemic exposure to harmaline rather than 5-MeO-DMT, although the body temperature profiles were mispredicted by the model. The results indicate that current PK/PD model may be used as a new conceptual framework to define the impact of serotonergic agents and stress factors on thermoregulation.
