Itraconazole, a potent inhibitor of P-glycoprotein, moderately increases plasma concentrations of oral morphine.
BACKGROUND
Individual variation in opioid response is considerable, partly due to pharmacokinetic factors. Transporter proteins are becoming increasingly interesting also in the pharmacokinetics of opioids. The efflux transporter P-glycoprotein can affect gastrointestinal absorption and tissue distribution, particularly brain access of many opioids. The aim of this study was to evaluate whether itraconazole, which is a potent inhibitor of P-glycoprotein and CYP3A4, would change the pharmacokinetics or the pharmacodynamics of oral morphine.


METHODS
Twelve healthy male volunteers ingested, in a randomized crossover study, once daily 200 mg itraconazole or placebo for 4 days. On day 4, 1 h after the last pre-treatment dose, the subjects ingested 0.3 mg/kg morphine. Blood samples for the determination of plasma morphine, morphine-3-glucuronide (M3G), morphine-6-glucuronide (M6G) and itraconazole concentrations were drawn up to 48 h after morphine ingestion. Pharmacodynamic effects were evaluated using a questionnaire, visual analogue scales, a reaction time test, the Digit Symbol Substitution Test and the Critical Flicker Fusion Test.


RESULTS
Itraconazole increased the mean area under the plasma concentration-time curve [AUC (0-9)] of morphine by 29% (P=0.002), its AUC (0-48) by 22% (P=0.013) and its peak plasma concentration by 28% (P=0.035). Itraconazole did not significantly affect the pharmacokinetic variables of M3G or M6G or the pharmacodynamic effects of morphine.


CONCLUSIONS
Itraconazole moderately increases plasma concentrations of oral morphine, probably by enhancing its absorption by inhibiting intestinal wall P-glycoprotein. A possible improvement of morphine penetration to the brain could not be observed.
Heiskanen
T
T
Pain Clinic, Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Central Hospital, Helsinki, Finland. tarja.heiskanen@hus.fi
Backman
J T
JT
Neuvonen
M
M
Kontinen
V K
VK
Neuvonen
P J
PJ
Kalso
E
E
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000097:blood; D000935:Antifungal Agents / Q000494:pharmacology*; D019540:Area Under Curve; D000697:Central Nervous System Stimulants / Q000097:blood; D018592:Cross-Over Studies; D004311:Double-Blind Method; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology*; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000097:blood; D009022:Morphine Derivatives / Q000097:blood; D010100:Oxygen / Q000097:blood; D010147:Pain Measurement; D012107:Research Design
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000701:Analgesics, Opioid; D000935:Antifungal Agents; D000697:Central Nervous System Stimulants; D009022:Morphine Derivatives; D017964:Itraconazole; C035349:morphine-6-glucuronide; D009020:Morphine; C018108:morphine-3-glucuronide; D010100:Oxygen