Semi-mechanistic pharmacokinetic/pharmacodynamic modelling of the antinociceptive response in the presence of competitive antagonism: the interaction between tramadol and its active metabolite on micro-opioid agonism and monoamine reuptake inhibition, in the rat.
OBJECTIVE
To establish a semi-mechanistic pharmacokinetic/pharmacodynamic (pk/pd) model for racemic tramadol (T) integrating all the components with a significant contribution to T effects in rats, using cold allodynia in the Bennett model of neuropathic pain.


METHODS
Male Sprague-Dawley rats (n=53) were randomly allocated in six groups receiving saline, racemic T (5 mg/kg), RR-T (5 mg/kg), SS-T (5 mg/kg), RR-O-demethyltramadol [RR-M1 (1 mg/kg)] or SS-M1 (30 mg/kg) in two h intravenous infusion.


RESULTS
The mu-opioid effects of RR-M1 (E(RR-M1)) were described with an effect compartment model. Contribution to analgesic response of RR-T resulted negligible. The monoamine re-uptake inhibition effects (ESS-M1,T) were modelled as an indirect response model incorporating a competitive interaction between SS-T and SS-M1. ERR-M1 and ESS-M1,T were finally considered as a two independent stimuli converging into a single and common antinoceptive stimulus. The estimates of the steady-state plasma concentrations eliciting half of maximum response for RR-M1, SS-T, and SS-M1 were 20.2, 230, and 869 ng/ml, respectively. RR-M1 is the main active component, but SS-T having a significant contribution.


CONCLUSIONS
Cold allodynia in the Bennett model has proven an adequate experimental set up to develop complex pk/pd models in analgesia involving different mechanisms of action.
Beier
Horst
H
Department of Pharmacokinetics, Grünenthal GmbH, 52078, Aachen, Germany.
Garrido
María J
MJ
Christoph
Thomas
T
Kasel
Dirk
D
Trocóniz
Iñaki F
IF
D000465:Algorithms; D000700:Analgesics / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003080:Cold Temperature; D003627:Data Interpretation, Statistical; D004347:Drug Interactions; D008297:Male; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists*; D014147:Tramadol / Q000493:pharmacokinetics / Q000494:pharmacology*
D000700:Analgesics; D000701:Analgesics, Opioid; D014179:Neurotransmitter Uptake Inhibitors; D017450:Receptors, Opioid, mu; D014147:Tramadol