title: Influence of concomitant quinidine administration on dextromethorphan disposition in rats.
abstract: High doses of dextromethorphan (DM) have been clinically investigated for the treatment of multiple neuronal disorders including neuropathic pain. Several authors have suggested the concomitant administration of DM and a CYP2D6 reversible inhibitor in order to enhance the exposure of DM and limit the exposure to total dextrorphan (DX). The present study proposes to determine whether or not a single dose of quinidine is sufficient to enhance the plasma concentrations of DM in rats and keep those of DX at a minimal level. Oral doses of DM (50 mg/kg) were administered with increasing dose levels of quinidine (0, 2, 20, and 50 mg/kg) to male Sprague-Dawley rats and blood samples were collected over 24 h. Plasma concentrations of DM and total DX were determined using ESI-LC/MS/MS. Quinidine coadministration resulted in a more than twofold increase in the area under the curve of DM with an ED(50) of approximately 2 mg/kg whereas those of total DX were only increased by 21%. These results support the working hypothesis that a single dose of quinidine may enhance the plasma concentrations of DM relative to those of total DX and may therefore improve the treatment of neuropathic pain.
authors.affiliation: MDS Pharma Services, Montreal, Quebec, Canada.
authors.forename: J F
authors.initials: JF
authors.lastname: Marier
authors.forename: L E
authors.initials: LE
authors.lastname: Pope
authors.forename: G J
authors.initials: GJ
authors.lastname: Yakatan
authors.forename: J E
authors.initials: JE
authors.lastname: Berg
authors.forename: M
authors.initials: M
authors.lastname: Stiles
authors.forename: P
authors.initials: P
authors.lastname: Vachon
mesh_terms: D000818:Animals; D000996:Antitussive Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D019540:Area Under Curve; D003915:Dextromethorphan / Q000378:metabolism / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D008657:Metabolic Clearance Rate; D011802:Quinidine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000996:Antitussive Agents; D004791:Enzyme Inhibitors; D003915:Dextromethorphan; D011802:Quinidine