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

Aims 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. Methods 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. Results 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