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

Abstract

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 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)).

Conclusions: 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.

Figures

Figure 1

Influence of quinidine on the miotic effects of IV methadone. Subjects received 10 mg IV methadone HCl as a 5 min infusion (shown as a solid bar in the insert), 1 h after quinidine (•) or placebo (○). Results are the change from baseline in dark-adapted pupil diameter, presented as the mean ± SD. The insert shows the first 20 min in greater detail. There were no significant differences between treatment groups

Figure 2

Influence of quinidine on miosis after IV methadone. Shown are peak miotic effects for each subject. Each set of data points is an individual subject, identified by a letter

Figure 3

Influence of quinidine on the disposition of (A) methadone and (B) EDDP. Subjects received 10 mg oral methadone HCl 1 h after quinidine (•) or placebo (○). Results are plasma concentrations (mean ± SD). Asterisks denote significant differences between treatment groups (P < 0.05)

Figure 4

Influence of quinidine on oral methadone effects. Results are the change from baseline in dark-adapted pupil diameter. Results as the mean ± SD (placebo (○), quinidine (•)). Asterisks denote significant differences between treatment groups (P < 0.05)

Figure 5

Influence of quinidine on the subjective effects of oral methadone. Attributes assessed (scored from 0 to 100) were sedation (almost asleep to wide awake), energy level (no energy to full energy), confusion (confused to clear headed), clumsiness (extremely clumsy to well coordinated), anxiety (calm to extremely nervous), and nausea (no nausea to worst nausea). Results are the mean (placebo (○), quinidine (•)). SDs are omitted for clarity. Asterisks denote significant differences between treatment groups (P < 0.05)

Figure 6

Influence of quinidine on the pharmacodynamics of oral methadone, shown as a counter-clockwise hysteresis plot. Each data point is the mean of 12 subjects, with SD omitted for clarity (placebo (○), quinidine (•))