Quinidine as a Probe for the Role of P‐Glycoprotein in the Intestinal Absorption and Clinical Effects of Fentanyl

Abstract

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 mm*h, 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 ng*h*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.

Pharmacokinetics and Pharmacodynamics of Alfentanil in P-Glycoprotein-Competent and P-Glycoprotein-Deficient Mice: P-Glycoprotein Efflux Alters Alfentanil Brain Disposition and Antinociception

“…The present results showing that alfentanil is a P-gp substrate indicate that alfentanil-pupillometry studies may have the potential to detect alterations in P-gp activity. Previous pupillometry studies conducted with the P-gp substrates morphine, fentanyl, methadone, and loperamide have shown that inhibition of P-gp at the BBB by the P-gp inhibitor quinidine is modest (Kharasch et al, 2003(Kharasch et al, , 2004aSkarke et al, 2003). Because quinidine is one of the most potent compounds capable of inhibiting P-gp that is in clinical use, the likelihood of significant inhibition of P-gp at the BBB seems remote.…”

Prediction of in vivo intestinal absorption enhancement on P-glycoprotein inhibition, from rat in situ permeability

“…6 However, these compounds have the strong affinity to P-gp and inhibit P-gpmediated efflux, and may show clinically significant increase in intestinal absorption of various P-gp substrates. 41,42 P-gp substrates belonging to class II (cyclosporine) are fairly permeable, and may be well absorbed into systemic circulation. However, low dissolution rate limits the concentration of the drug at the site of absorption, thereby leading to less passive diffusion and further preventing saturation of efflux transporter.…”

Controlling Drug Release in Oral Product Development Programs: An Industrial Perspective

“…Some excipients are also Pgp inhibitors but these do not come within the scope of this article. CYP450 inhibitors such as quinidine can also enhance the bioavailability of CYP450-susceptible drugs on pre or coadministration [2]. However, this strategy may complicate the coadministration of other medications that are also CYP450-susceptibile; the bioavailability of concurrently administered medication might also be altered.…”