Kharasch Evan D, Hoffer Christine, Altuntas T Gul, Whittington Dale
Department of Anesthesiology, Box 356540, University of Washington, 1959 NE Pacific St. RR-442, Seattle, WA 98195, USA.
J Clin Pharmacol. 2004 Mar;44(3):224-33. doi: 10.1177/0091270003262075.
The mechanism of individual variability in the fentanyl dose-effect relationship is unknown. The efflux pump P-glycoprotein (P-gp) regulates brain access and intestinal absorption of numerous drugs. Evidence exists that fentanyl is a P-gp substrate in vitro, and P-gp affects fentanyl analgesia in animals. However, the role of P-gp in human fentanyl disposition and clinical effects is unknown. This investigation tested the hypothesis that plasma concentrations and clinical effects of oral and intravenous fentanyl 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, two-period crossover studies were conducted in normal healthy volunteers (6 males and 6 females) after obtaining informed consent. Pupil diameters and/or plasma concentrations of fentanyl and norfentanyl were evaluated after oral or intravenous fentanyl (2.5 microg/kg), dosed 1 hour after oral quinidine (600 mg) or placebo. Quinidine did not alter the magnitude or time to maximum miosis, time-specific pupil diameter, or subjective self-assessments after intravenous fentanyl but did increase the area under the curve (AUC) of miosis versus time (13.6 +/- 5.3 vs. 8.7 +/- 5.0 mmh, p< 0.05) and decreased the effect of elimination (k(el) 0.35 +/- 0.16 vs. 0.52 +/- 0.24 h(-1), p < 0.05). Quinidine increased oral fentanyl plasma C(max) (0.55 +/- 0.19 vs. 0.21 +/- 0.1 ng/mL) and AUC (1.9 +/- 0.5 vs. 0.7 +/- 0.3 ngh*mL(-1)) (both p < 0.05) but had no effect on apparent elimination. Plasma norfentanyl/fentanyl AUC ratios were not diminished by quinidine. Quinidine significantly increased maximum miosis after oral fentanyl (3.4 +/- 1.3 vs. 2.3 +/- 1.3 mm, p< 0.05), commensurate with increases in plasma concentrations, but concentration-effect relationships and the rate constant for the transfer between plasma and effect compartment (k(e0)) (1.9 +/- 1.0 vs. 3.6 +/- 2.6 h(-1)) were not significantly different. Quinidine increased oral fentanyl plasma concentrations, suggesting that intestinal P-gp or some other quinidine-sensitive transporter affects the absorption, bioavailability, and hence clinical effects of oral fentanyl. Quinidine had less effect on fentanyl pharmacodynamics, suggesting that if quinidine is an effective inhibitor of brain P-gp, then P-gp appears to have less effect on brain access of fentanyl.
芬太尼剂量 - 效应关系中个体差异的机制尚不清楚。外排泵P - 糖蛋白（P - gp）调节多种药物的脑内进入和肠道吸收。有证据表明芬太尼在体外是P - gp的底物，并且P - gp影响动物的芬太尼镇痛作用。然而，P - gp在人体芬太尼处置和临床效应中的作用尚不清楚。本研究使用P - gp抑制剂奎尼丁作为体内探针，检验了以下假设：在抑制肠道和脑P - gp后，口服和静脉注射芬太尼的血浆浓度和临床效应会更高。在获得知情同意后，对正常健康志愿者（6名男性和6名女性）进行了两项随机、双盲、安慰剂对照、平衡、两期交叉研究。在口服奎尼丁（600 mg）或安慰剂1小时后，给予口服或静脉注射芬太尼（2.5μg/kg），随后评估瞳孔直径和/或芬太尼及去甲芬太尼的血浆浓度。奎尼丁并未改变静脉注射芬太尼后的最大瞳孔缩小幅度、达到最大瞳孔缩小的时间、特定时间的瞳孔直径或主观自我评估，但确实增加了瞳孔缩小面积与时间的曲线下面积（AUC）（13.6± 5.3对8.7±5.0 mm·h，p<0.05），并降低了消除效应（k(el) 0.35±0.16对0.52±0.24 h(-1)，p <0.05）。奎尼丁增加了口服芬太尼的血浆C(max)（0.55±0.19对0.21±0.1 ng/mL）和AUC（1.9±0.5对0.7±0.3 ng·h·mL(-1)）（两者p <0.05），但对表观消除无影响。奎尼丁并未降低血浆去甲芬太尼/芬太尼AUC比值。奎尼丁显著增加了口服芬太尼后的最大瞳孔缩小（3.4±1.3对2.3±1.3 mm，p<0.05），与血浆浓度增加一致，但浓度 - 效应关系以及血浆与效应室之间转移的速率常数（k(e0)）（1.9±1.0对3.6±2.6 h(-1)）无显著差异。奎尼丁增加了口服芬太尼的血浆浓度，表明肠道P - gp或其他对奎尼丁敏感的转运体影响口服芬太尼的吸收、生物利用度，进而影响其临床效应。奎尼丁对芬太尼药效学的影响较小，表明如果奎尼丁是脑P - gp的有效抑制剂，那么P - gp似乎对芬太尼进入脑内的影响较小。
