Influence of concomitant quinidine administration on dextromethorphan disposition in rats.
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.
Marier
J F
JF
MDS Pharma Services, Montreal, Quebec, Canada.
Pope
L E
LE
Yakatan
G J
GJ
Berg
J E
JE
Stiles
M
M
Vachon
P
P
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
D000996:Antitussive Agents; D004791:Enzyme Inhibitors; D003915:Dextromethorphan; D011802:Quinidine