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-HT1A receptor and thermogenesis via the stimulation of 5-HT2A receptor, 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 SC50 value (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.

A population analysis of the DGAT1 inhibitor GSK3008356 and its effect on endogenous and meal‐induced triglyceride turnover in healthy subjects

“…To evaluate a possible negative feedback mechanism involved in TG regulation, the indirect response model was tested to include a term to account for an adaptive feedback mechanism . In this model, the feedback function is described as a ratio of TG baseline (Base) to TG levels (i.e., ) and would affect the total TG production rate ( K in ).…”

A narrative synthesis of research with 5-MeO-DMT

“…5-MeO-DMT dose dependently reduces locomotor activity, reduces investigatory behaviour but induces forepaw treading, flat-body posture, Straub tail response and hindlimb abduction. This appears to be mainly mediated through 5-HT 1A receptors, with some contribution of 5-HT 2A receptors ( Bedard and Pycock, 1977 ; Castellanos et al, 2020 ; Eide and Tjølsen, 1988 ; Halberstadt, 2016 ; Halberstadt et al, 2008 , 2011 , 2012 ; Jiang et al, 2016b ; Krebs-Thomson et al, 2006 ; Matsumoto et al, 1997 ; Matthews and Smith, 1980 ; Rigdon and Weatherspoon, 1992 ; Smith and Peroutka, 1986 ; Tricklebank et al, 1985 ; Van den Buuse et al, 2011 ). 5-MeO-DMT at high doses inhibits shock-elicited fighting in rats ( Walters et al, 1978 ).…”

“…5-HT 2A receptor-related vasoconstriction is thought to be a main effector site of serotonergic thermoregulation ( Ootsuka et al, 2004 ). Using an experimental drug administration and mathematical pharmacokinetic/pharmacodynamic (PK/PD) model, Jiang et al (2016b) demonstrated that 5-MeO-DMT induces transient hyperthermia in mice. However, another study showed that 3 mg/kg 5-MeO-DMT reduced tail-skin temperature in mice by 1.8°C ( Eide and Tjølsen, 1988 ).…”

“…Coadministration of even a relatively low dose of harmaline (an inhibitor of monoamine oxidase) readily blocks MAO A -dependent elimination in mice, shifting 5-MeO-DMT metabolism to alternative pathways such as O-demethylation. This leads to a greater rate of conversion to bufotenine and significantly extends systemic and central exposure to 5-MeO-DMT ( Halberstadt, 2016 ; Halberstadt et al, 2008 , 2012 ; Jiang et al, 2016b ; Shen et al, 2010b ). In contrast, chronic treatment with MAO inhibitors suppresses response to 5-MeO-DMT in rodents ( Gudelsky et al, 1986b ; Lucki and Frazer, 1982 ).…”

Advanced knowledge in drug metabolism and pharmacokinetics

“…Wenli Liu and colleagues use nimodipine as a model drug to demonstrate the potential effects of age and polymorphic form on pharmacokinetics in rats 12 . Xi-ling Jiang and colleagues describe the development of a new mechanism-based PK/PD model to characterize the thermoregulatory effects of serotonergic drugs in mouse models, which may serve as a new framework for the investigation of thermoregulatory or other neuropharmacological effects of serotonergic agents 13 .…”