Interactions of fentanyl with blood platelets and plasma proteins: platelet sensitivity to prasugrel metabolite is not affected by fentanyl under in vitro conditions

Pharmacol Rep. 2023 Apr;75(2):423-441. doi: 10.1007/s43440-023-00447-7. Epub 2023 Jan 17.

Abstract

Background: Clinical trials indicate that fentanyl, like morphine, may impair intestinal absorption and thus decrease the efficacy of oral P2Y12 inhibitors, such as clopidogrel, ticagrelor, and prasugrel. However, the ability of fentanyl to directly negate or reduce the inhibitory effect of P2Y12 receptor antagonists on platelet function has not been established. A series of in vitro experiments was performed to investigate the ability of fentanyl to activate platelets, potentiate platelet response to ADP, and/or diminish platelet sensitivity to prasugrel metabolite (R-138727) in agonist-stimulated platelets. The selectivity and specificity of fentanyl toward major carrier proteins has been also studied.

Methods: Blood was obtained from healthy volunteers (19 women and 12 men; mean age 40 ± 13 years). Platelet function was measured in whole blood, platelet-rich plasma and in suspensions of isolated platelets by flow cytometry, impedance and optical aggregometry. Surface plasmon resonance and molecular docking were employed to determine the binding kinetics of fentanyl to human albumin, α1-acid glycoprotein, apolipoprotein A-1 and apolipoprotein B-100.

Results: When applied at therapeutic and supratherapeutic concentrations under various experimental conditions, fentanyl had no potential to stimulate platelet activation and aggregation, or potentiate platelet response to ADP, nor did it affect platelet susceptibility to prasugrel metabolite in ADP-stimulated platelets. In addition, fentanyl was found to interact with all the examined carrier proteins with dissociation constants in the order of 10-4 to 10-9 M.

Conclusions: It does not seem that the delayed platelet responsiveness to oral P2Y12 inhibitors, such as prasugrel, in patients undergoing percutaneous coronary intervention, results from direct interactions between fentanyl and blood platelets. Apolipoproteins, similarly to albumin and α1-acid glycoprotein, appear to be important carriers of fentanyl in blood.

Keywords: Antiplatelet therapy; Blood platelets; Drug carriers; Fentanyl; Platelet activation; Protein binding.

MeSH terms

  • Adult
  • Blood Platelets*
  • Female
  • Fentanyl / pharmacology
  • Humans
  • Male
  • Middle Aged
  • Molecular Docking Simulation
  • Orosomucoid / metabolism
  • Orosomucoid / pharmacology
  • Platelet Aggregation
  • Platelet Aggregation Inhibitors* / pharmacology
  • Prasugrel Hydrochloride / pharmacology
  • Purinergic P2Y Receptor Antagonists / pharmacology

Substances

  • Prasugrel Hydrochloride
  • Platelet Aggregation Inhibitors
  • Orosomucoid
  • Fentanyl
  • Purinergic P2Y Receptor Antagonists