title: Pharmacokinetic/pharmacodynamic modeling of the antinociceptive effects of (+)-tramadol in the rat: role of cytochrome P450 2D activity.
abstract: In this study the role of cytochrome P450 2D (CYP2D) in the pharmacokinetic/pharmacodynamic relationship of (+)-tramadol [(+)-T] has been explored in rats. Male Wistar rats were infused with (+)-T in the absence of and during pretreatment with a reversible CYP2D inhibitor quinine (Q), determining plasma concentrations of Q, (+)-T, and (+)-O-demethyltramadol [(+)-M1], and measuring antinociception. Pharmacokinetics of (+)-M1, but not (+)-T, was affected by Q pretreatment: early after the start of (+)-T infusion, levels of (+)-M1 were significantly lower (P < 0.05). However, at later times during Q infusion those levels increased continuously, exceeding the values found in animals that did not receive the inhibitor. These results suggest that CYP2D is involved in the formation and elimination of (+)-M1. In fact, results from another experiment where (+)-M1 was given in the presence and in absence of Q showed that (+)-M1 elimination clearance (CL(ME0)) was significantly lower (P < 0.05) in animals receiving Q. Inhibition of both (+)-M1 formation clearance (CL(M10)) and CL(ME0) were modeled by an inhibitory E(MAX) model, and the estimates (relative standard error) of the maximum degree of inhibition (E(MAX)) and IC(50), plasma concentration of Q eliciting half of E(MAX) for CL(M10) and CL(ME0), were 0.94 (0.04), 97 (0.51) ng/ml, and 48 (0.42) ng/ml, respectively. The modeling of the time course of antinociception showed that the contribution of (+)-T was negligible and (+)-M1 was responsible for the observed effects, which depend linearly on (+)-M1 effect site concentrations. Therefore, the CYP2D activity is a major determinant of the antinociception elicited after (+)-T administration.
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona 31080, Spain.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Garrido
authors.forename: Onintza
authors.initials: O
authors.lastname: Sayar
authors.forename: Cristina
authors.initials: C
authors.lastname: Segura
authors.forename: Javier
authors.initials: J
authors.lastname: Rapado
authors.forename: Maria Carmen
authors.initials: MC
authors.lastname: Dios-Vieitez
authors.forename: Maria Jesus
authors.initials: MJ
authors.lastname: Renedo
authors.forename: Inaki F
authors.initials: IF
authors.lastname: Troconiz
mesh_terms: D000465:Algorithms; D000701:Analgesics, Opioid / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007262:Infusions, Intravenous; D008297:Male; D008954:Models, Biological; D011803:Quinine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014147:Tramadol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D000701:Analgesics, Opioid; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; C080580:O-demethyltramadol; D014147:Tramadol; D011803:Quinine; D019389:Cytochrome P-450 CYP2D6