title: Pharmacokinetic-pharmacodynamic modeling of the antinociceptive effects of main active metabolites of tramadol, (+)-O-desmethyltramadol and (-)-O-desmethyltramadol, in rats.
abstract: The pharmacokinetics and pharmacodynamics of the two main metabolites of tramadol, (+)-O-desmethyltramadol and (-)-O-desmethyltramadol, were studied in rats. Pharmacodynamic endpoints evaluated were respiratory depression, measured as the change in arterial blood pCO(2), pO(2), and pH levels; and antinociception, measured by the tail-flick technique. The administration of 10 mg/kg (+)-O-desmethyltramadol in a 10-min i.v. infusion significantly altered pCO(2), pO(2), and pH values in comparison with baseline and lower-dose groups (P <.05). However, 2 mg/kg administered in a 10-min i.v. infusion was enough to achieve 100% antinociception without respiratory depression. Moreover, the beta-funaltrexamine pretreatment completely eliminated the antinociception of the 2-mg/kg dose, suggesting that such an effect is due to mu-opioid receptor activation. To describe and adequately characterize the in vivo antinociceptive effect of the drug, (+)-O-desmethyltramadol was given at different infusion rates of varying lengths (10-300 min). Pharmacokinetics was best described by a two-compartmental model. The time course of response was described using an effect compartment associated with a linear pharmacodynamic model. The estimates of the slope of the effect versus concentration relationship were significantly decreased (P <. 05) as the length of infusion was increased, suggesting the development of tolerance. Doses of up to 8 mg/kg (-)-O-desmethyltramadol given in 10-min i.v. infusion did not elicit either antinociception in the tail-flick test or respiratory effects. These in vivo results are in accordance with the opiate and nonopiate properties reported for these compounds in several in vitro studies.
authors.affiliation: Department of Pharmacology, School of Medicine, University of Basque Country, Leioa, Bizkaia, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Valle
authors.forename: M J
authors.initials: MJ
authors.lastname: Garrido
authors.forename: J M
authors.initials: JM
authors.lastname: Pavón
authors.forename: R
authors.initials: R
authors.lastname: Calvo
authors.forename: I F
authors.initials: IF
authors.lastname: Trocóniz
mesh_terms: D000465:Algorithms; D000701:Analgesics, Opioid / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000818:Animals; D006863:Hydrogen-Ion Concentration; D008297:Male; D008954:Models, Biological; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015656:Respiratory Mechanics / Q000187:drug effects; D013237:Stereoisomerism; D013997:Time Factors; D014147:Tramadol / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000701:Analgesics, Opioid; C080580:O-demethyltramadol; D014147:Tramadol; D009271:Naltrexone; C024524:beta-funaltrexamine