title: Development of a mechanism-based pharmacokinetic/pharmacodynamic model to characterize the thermoregulatory effects of serotonergic drugs in mice.
abstract: We have shown recently that concurrent harmaline, a monoamine oxidase-A inhibitor (MAOI), potentiates serotonin (5-HT) receptor agonist 5-methoxy-N,N-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-HT1Areceptor and thermogenesisviathe stimulation of 5-HT2Areceptor, 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 SC50value (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.
authors.affiliation: 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.
authors.forename: Xi-Ling
authors.initials: XL
authors.lastname: Jiang
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214-8033, USA.
authors.forename: Hong-Wu
authors.initials: HW
authors.lastname: Shen
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214-8033, USA.
authors.forename: Donald E
authors.initials: DE
authors.lastname: Mager
authors.affiliation: Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, University of Florida, Orlando, FL 32827, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: Department of Biochemistry & Molecular Medicine, UC Davis School of Medicine, 2700 Stockton Boulevard, Sacramento, CA 95817, USA.
authors.forename: Ai-Ming
authors.initials: AM
authors.lastname: Yu
keywords: Indolealkylamine; Monoamine oxidase-A inhibitor; PK/PD model; Serotonin; Stress; Thermoregulation