Intracellular uptake of agents that block the hERG channel can confound the assessment of QT interval prolongation and arrhythmic risk

Heart Rhythm. 2021 Dec;18(12):2177-2186. doi: 10.1016/j.hrthm.2021.08.028. Epub 2021 Sep 2.

Abstract

Background: Oliceridine is a biased ligand at the μ-opioid receptor recently approved for the treatment of acute pain. In a thorough QT study, corrected QT (QTc) prolongation displayed peaks at 2.5 and 60 minutes after a supratherapeutic dose. The mean plasma concentration peaked at 5 minutes, declining rapidly thereafter.

Objective: The purpose of this study was to examine the basis for the delayed effect of oliceridine to prolong the QTc interval.

Methods: Repolarization parameters and tissue accumulation of oliceridine were evaluated in rabbit left ventricular wedge preparations over a period of 5 hours. The effects of oliceridine on ion channel currents were evaluated in human embryonic kidney and Chinese hamster ovary cells. Quinidine was used as a control.

Results: Oliceridine and quinidine produced a progressive prolongation of the QTc interval and action potential duration over a period of 5 hours, paralleling slow progressive tissue uptake of the drugs. Oliceridine caused modest prolongation of these parameters, whereas quinidine produced a prominent prolongation of action potential duration and QTc interval as well as development of early afterdepolarization (after 2 hours), resulting in a high torsades de pointes score. The 50% inhibitory concentration values for the oliceridine inhibition of the rapidly activating delayed rectifier current (human ether a-go-go current) and late sodium channel current were 2.2 and 3.45 μM when assessed after traditional acute exposure but much lower after 3 hours of drug exposure.

Conclusion: Our findings suggest that a gradual increase of intracellular access of drugs to the hERG channels as a result of their intracellular uptake and accumulation can significantly delay effects on repolarization, thus confounding the assessment of QT interval prolongation and arrhythmic risk when studied acutely. The multi-ion channel effects of oliceridine, late sodium channel current inhibition in particular, point to a low risk of devloping torsades de pointes.

Keywords: Acquired long QT syndrome; Opiates; Opioids; Pharmacokinetic-pharmacodynamic models; Pharmacology; Quinidine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / pharmacokinetics
  • Animals
  • Arrhythmias, Cardiac* / etiology
  • Arrhythmias, Cardiac* / metabolism
  • Arrhythmias, Cardiac* / physiopathology
  • Arrhythmias, Cardiac* / prevention & control
  • Cell Line
  • Cricetulus
  • ERG1 Potassium Channel / antagonists & inhibitors*
  • Humans
  • Inhibitory Concentration 50
  • Long QT Syndrome / chemically induced
  • Long QT Syndrome / metabolism
  • Long QT Syndrome / physiopathology
  • Membrane Transport Modulators / pharmacology
  • Quinidine / pharmacokinetics
  • Spiro Compounds / pharmacokinetics*
  • Thiophenes / pharmacokinetics*
  • Tissue Distribution
  • Voltage-Gated Sodium Channel Blockers / pharmacokinetics

Substances

  • ((3-methoxythiophen-2-yl)methyl)((2-(9-(pyridin-2-yl)-6-oxaspiro(4.5)decan-9-yl)ethyl))amine
  • Analgesics, Opioid
  • ERG1 Potassium Channel
  • Membrane Transport Modulators
  • Spiro Compounds
  • Thiophenes
  • Voltage-Gated Sodium Channel Blockers
  • Quinidine