Abstract
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. 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. 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. 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.
Published Version
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