Effects of quinidine on antinociception and pharmacokinetics of morphine in rats.
OBJECTIVE
The aim of this study was to investigate the effect of quinidine, a P-glycoprotein inhibitor, on the pharmacokinetics and pharmacodynamics of morphine in rats.


METHODS
Rats were given morphine (30 mg/kg p.o. or 30 mg/kg over 10 min i.v.) 30 min after pretreatment with quinidine (30 mg/kg p.o.). Antinociceptive effects were determined using the tail immersion test. Concentrations of morphine in plasma and brain were also determined.


RESULTS
The antinociception of morphine was significantly enhanced by oral administration of quinidine, with a 3.1-fold greater area under the effect-time curve than that in vehicle-treated rats. Morphine concentrations in plasma and brain were significantly increased by quinidine. The area under the plasma concentration-time curve after oral or intravenous administration of morphine was increased 5.2- and 1.7-fold, respectively, in quinidine-pretreated rats compared with vehicle-pretreated rats. Quinidine caused a 40% decrease in the total clearance of morphine and increased the concentration of morphine in the brain, although the brain-to-plasma concentration ratio was not changed.


CONCLUSIONS
Oral administration of quinidine increases the absorption of morphine from the gastrointestinal tract and subsequently enhances the concentration in the brain and its antinociceptive effect. Enhanced intestinal absorption of morphine may be due largely to inhibition of intestinal P-glycoprotein by quinidine.
Okura
Takashi
T
Department of Pharmacokinetics, Pharmacodynamics, Global Center of Excellence (COE) and Clinical Pharmaceutics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
Morita
Yuki
Y
Ito
Yoshihiko
Y
Kagawa
Yoshiyuki
Y
Yamada
Shizuo
S
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000284:Administration, Oral; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D019540:Area Under Curve; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D007275:Injections, Intravenous; D007408:Intestinal Absorption / Q000187:drug effects; D008297:Male; D008657:Metabolic Clearance Rate; D009020:Morphine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D010147:Pain Measurement; D011802:Quinidine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000317:Adrenergic alpha-Antagonists; D000701:Analgesics, Opioid; D009020:Morphine; D011802:Quinidine