Development of a mechanism-based pharmacokinetic/pharmacodynamic model to characterize the thermoregulatory effects of serotonergic drugs in mice

摘要

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-Me O-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-Me O-DMT–elicited hyperthermia were attributable to the loss of heat through the activation of 5-HT1 Areceptor and thermogenesis via the stimulation of 5-HT2 Areceptor,respectively.Thus serotonergic 5-Me O-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 on5-Me O-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 SC50 value（1.88–0.496 mmol/L） for 5-Me O-DMT when harmaline was co-administered,providing a quantitative assessment for the impact of concurrent MAOI harmaline on 5-Me ODMT–induced hyperthermia.In addition,the hyperpyrexia caused by toxic dose combinations of harmaline and 5-Me O-DMT were linked to the increased systemic exposure to harmaline rather than5-Me O-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.