Kharasch Evan D, Hoffer Christine, Whittington Dale
Department of Anaesthesiology, University of Washington, Seattle, WA 98195, USA.
Br J Clin Pharmacol. 2004 May;57(5):600-10. doi: 10.1111/j.1365-2125.2003.02053.x.
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 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)).
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.
美沙酮剂量效应关系中存在大量无法解释的个体间差异。外排泵P-糖蛋白（P-gp）可调节多种药物的脑内摄取和肠道吸收。有证据表明，美沙酮在体外是P-gp的底物，且P-gp会影响动物的美沙酮镇痛效果。然而，P-gp在人体美沙酮处置和药效学中的作用尚不清楚。本研究以P-gp抑制剂奎尼丁作为体内探针，检验了如下假设：抑制肠道和脑内P-gp后，口服和静脉注射美沙酮的肠道吸收和药效学会增强。
在健康受试者中进行了两项随机、双盲、安慰剂对照、平衡交叉研究。在口服奎尼丁（600 mg）或安慰剂1小时后，给予10 mg盐酸美沙酮静脉注射或口服，然后测量美沙酮及其主要代谢产物EDDP的瞳孔直径和/或血浆浓度。
奎尼丁未改变静脉注射美沙酮的效应。瞳孔缩小的达峰时间（t(max)）（0.3±0.3 vs 0.3±0.2小时（-0.17，0.22））、峰值（5.3±0.8 vs 5.1±1.0 mm（0.39，0.84））以及药时曲线下面积（AUC）（25.0±5.7 vs 26.8±7.1 mm·小时（-6.1，2.5））均未改变（安慰剂组与奎尼丁组（差异的95%置信区间））。口服美沙酮后，奎尼丁使吸收期血浆美沙酮浓度升高（P<0.05），t(max)降低（2.4±0.7 vs 1.6±0.9小时（0.33，1.2）），瞳孔缩小峰值增大（3.2±1.5 vs 4.3±1.6 mm（-1.96，-0.19））。美沙酮的C(max)（55.6±10.3 vs 59.4±14.1 ng/ml（-8.5，0.65））和AUC（298±46 vs 316±74 ng/ml·小时（-54，18））未改变，EDDP与美沙酮的AUC比值也未改变。奎尼丁对美沙酮在血浆和效应室之间转移的速率常数（k(e0)）没有影响（2.6±2.6 vs 2.5±1.4小时-1（-3.5，4.2））。
奎尼丁增加了口服美沙酮吸收期的血浆浓度以及美沙酮引起的瞳孔缩小，表明肠道P-gp影响口服美沙酮的吸收，进而影响其临床效果。静脉注射给药后，奎尼丁对美沙酮药效学没有影响，这表明如果奎尼丁是脑内P-gp的有效抑制剂，那么P-gp似乎不是美沙酮进入脑内的决定因素。
