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.
RCT Entities:
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.
Authors: Juha Grönlund; Teijo I Saari; Nora M Hagelberg; Pertti J Neuvonen; Klaus T Olkkola; Kari Laine Journal: Br J Clin Pharmacol Date: 2010-07 Impact factor: 4.335
Authors: Stacy S Shord; Lingtak-Neander Chan; Joseph R Camp; Eva M Vasquez; Hyun-Young Jeong; Robert E Molokie; Charles L Baum; Hui Xie Journal: Br J Clin Pharmacol Date: 2010-02 Impact factor: 4.335