• Evan D Kharasch, Christine Hoffer, and Dale Whittington.
• Department of Anaesthesiology, University of Washington, Seattle, WA 98195, USA. kharasch@u.washington.edu
• Br J Clin Pharmacol. 2004 May 1;57(5):600-10.

AimsThere is considerable unexplained interindividual variability in the methadone dose-effect relationship. The efflux pump P-glycoprotein (P-gp) regulates brain access and intestinal absorption of many drugs. Evidence suggests that methadone is a P-gp substrate in vitro, and P-gp affects methadone analgesia in animals. However the role of P-gp in human methadone disposition and pharmacodynamics is unknown. This investigation tested the hypothesis that the intestinal absorption and pharmacodynamics of oral and intravenous methadone are greater after inhibition of intestinal and brain P-gp, using the P-gp inhibitor quinidine as an in vivo probe.MethodsTwo randomized, double-blind, placebo-controlled, balanced crossover studies were conducted in healthy subjects. Pupil diameters and/or plasma concentrations of methadone and the primary metabolite EDDP were measured after 10 mg intravenous or oral methadone HCl, dosed 1 h after oral quinidine (600 mg) or placebo.ResultsQuinidine did not alter the effects of intravenous methadone. Miosis t(max) (0.3 +/- 0.3 vs 0.3 +/- 0.2 h (-0.17, 0.22)), peak (5.3 +/- 0.8 vs 5.1 +/- 1.0 mm (0.39, 0.84)) and AUC vs time (25.0 +/- 5.7 vs 26.8 +/- 7.1 mm h (-6.1, 2.5)) were unchanged (placebo vs quinidine (95% confidence interval on the difference)). Quinidine increased (P < 0.05) plasma methadone concentrations during the absorptive phase, decreased t(max) (2.4 +/- 0.7 vs 1.6 +/- 0.9 h (0.33, 1.2)), and increased peak miosis (3.2 +/- 1.5 vs 4.3 +/- 1.6 mm (-1.96, -0.19)) after oral methadone. The C(max) (55.6 +/- 10.3 vs 59.4 +/- 14.1 ng ml(-1) (-8.5, 0.65)) and AUC of methadone (298 +/- 46 vs 316 +/- 74 ng ml(-1) h (-54, 18)) were unchanged, as were the EDDP : methadone AUC ratios. Quinidine had no effect on the rate constant for transfer of methadone between plasma and effect compartment (k(e0)) (2.6 +/- 2.6 vs 2.5 +/- 1.4 h(-1) (-3.5, 4.2)).ConclusionsQuinidine increased the plasma concentrations of oral methadone in the absorptive phase and the miosis caused by methadone, suggesting that intestinal P-gp affects oral methadone absorption and hence its clinical effects. Quinidine had no effect on methadone pharmacodynamics after intravenous administration, suggesting that if quinidine is an effective inhibitor of brain P-gp, then P-gp does not appear to be a determinant of the access of methadone to the brain.

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