The effect of quinidine, used as a probe for the involvement of P‐glycoprotein, on the intestinal absorption and pharmacodynamics of methadone

Article date: May 2004

By: Evan D. Kharasch, Christine Hoffer, Dale Whittington, in Volume 57, Issue 5, pages 600-610


There 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.


Two 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.


Quinidine did not alter the effects of intravenous methadone. Miosis tmax (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 tmax (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 Cmax (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 (ke0) (2.6 ± 2.6 vs 2.5 ± 1.4 h−1 (−3.5, 4.2)).


Quinidine 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.

DOI: 10.1111/j.1365-2125.2003.02053.x

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