Respiratory and miotic effects of morphine in healthy volunteers when P-glycoprotein is blocked by quinidine.
OBJECTIVE
Our objective was to evaluate whether P-glycoprotein inhibition after quinidine pretreatment results in modified central nervous effects of morphine.


METHODS
Twelve healthy volunteers received 7.5 mg morphine as an intravenous infusion over a 3-hour period. In a randomized, double-blind, 2-way crossover fashion, subjects received either 800 mg quinidine or placebo 1 hour before the start of morphine administration. The miotic and respiratory depressive effects of morphine were assessed by means of pupillometry and the respiratory response to carbon dioxide rebreathing, respectively. Quinidine effects were assessed by electrocardiogram recordings. Plasma concentrations of morphine and its glucuronide metabolites were measured throughout the observation period of 5 hours.


RESULTS
Morphine significantly reduced both the respiratory response to carbon dioxide and the pupil diameter. Throughout the observation period, quinidine had significant effects on the corrected QT interval (QTc increase of >60 milliseconds), indicating clinically relevant quinidine action. However, quinidine pretreatment did not enhance the respiratory depressive effects of morphine, nor did it alter the miotic effects of morphine to a statistically significant or clinically relevant extent. Plasma concentrations of morphine and its glucuronides were not significantly changed by quinidine pretreatment.


CONCLUSIONS
Whereas morphine clearly produced miosis and respiratory depression, pretreatment with quinidine as an inhibitor of P-glycoprotein did not result in an enhancement of central nervous opioid effects in healthy volunteers.
Skarke
Carsten
C
pharmazentrum frankfurt, Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany. skarke@em.uni-frankfurt.de
Jarrar
Marwan
M
Erb
Katharina
K
Schmidt
Helmut
H
Geisslinger
Gerd
G
Lötsch
Jörn
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000328:Adult; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D015877:Miosis / Q000139:chemically induced*; D009020:Morphine / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D010147:Pain Measurement; D011802:Quinidine / Q000494:pharmacology*; D012119:Respiration / Q000187:drug effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000317:Adrenergic alpha-Antagonists; D009020:Morphine; D011802:Quinidine