Mechanisms of QT prolongation by buprenorphine cannot be explained by direct hERG channel block
[3];
[6];
[7];
[3]
- U.S. Food and Drug Administration (FDA), Silver Spring, MD (United States). Center for Drug Evaluation and Research and Center for Devices and Radiological Health
- U.S. Food and Drug Administration (FDA), Silver Spring, MD (United States). Center for Drug Evaluation and Research; CiPALab, Gaithersburg, MD (United States)
- U.S. Food and Drug Administration (FDA), Silver Spring, MD (United States). Center for Drug Evaluation and Research
- U.S. Food and Drug Administration (FDA), Silver Spring, MD (United States). Center for Drug Evaluation and Research; Vertex Pharmaceuticals (Europe) Ltd., Abingdon (United Kingdom)
- U.S. Food and Drug Administration (FDA), Silver Spring, MD (United States). Center for Drug Evaluation and Research and Center for Devices and Radiological Health
- U.S. Food and Drug Administration (FDA), Silver Spring, MD (United States). Center for Devices and Radiological Health; Massachusetts General Hospital, Boston, MA (United States). Cardiovascular Research Center; Harvard Medical School, Boston, MA (United States)
- U.S. Food and Drug Administration (FDA), Silver Spring, MD (United States). Center for Devices and Radiological Health
Buprenorphine is a μ-opioid receptor (MOR) partial agonist used to manage pain and addiction. QTC prolongation that crosses the 10 msec threshold of regulatory concern was observed at a supratherapeutic dose in two thorough QT studies for the transdermal buprenorphine product BUTRANS®. Because QTC prolongation can be associated with Torsades de Pointes (TdP), a rare but potentially fatal ventricular arrhythmia, these results have led to further investigation of the electrophysiological effects of buprenorphine. Drug-induced QTC prolongation and TdP are most commonly caused by acute inhibition of hERG current (IhERG) that contribute to the repolarizing phase of the ventricular action potentials (APs). Concomitant inhibition of inward late Na+ (INaL) and/or L-type Ca2+ (ICaL) current can offer some protection against proarrhythmia. Therefore, we characterized the effects of buprenorphine and its major metabolite norbuprenorphine on cardiac hERG, Ca2+, and Na+ ion channels, as well as cardiac APs. For comparison, methadone, a MOR agonist associated with QTC prolongation and high TdP risk, and naltrexone and naloxone, two opioid receptor antagonists, were also studied. Whole cell recordings were performed at 37°C on cells stably expressing hERG, CaV1.2, and NaV1.5 proteins. Microelectrode array (MEA) recordings were made on human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). The results showed that buprenorphine, norbuprenorphine, naltrexone, and naloxone had no effect on IhERG, ICaL, INaL, and peak Na+ current (INaP) at clinically relevant concentrations. In contrast, methadone inhibited IhERG, ICaL, and INaL. Experiments on iPSC-CMs showed a lack of effect for buprenorphine, norbuprenorphine, naltrexone, and naloxone, and delayed repolarization for methadone at clinically relevant concentrations. The mechanism of QTC prolongation is opioid moiety-specific. This remains undefined for buprenorphine, while for methadone it involves direct hERG channel block. There is no evidence that buprenorphine use is associated with TdP. Whether this lack of TdP risk can be generalized to other drugs with QTC prolongation not mediated by acute hERG channel block warrants further study.
- Research Organization:
- Oak Ridge Inst. for Science and Education (ORISE), Oak Ridge, TN (United States)
- Sponsoring Organization:
- USDOE Office of Science (SC); U.S. Food and Drug Administration (FDA)
- Grant/Contract Number:
- SC0014664
- OSTI ID:
- 1904961
- Journal Information:
- PLoS ONE, Vol. 15, Issue 11; ISSN 1932-6203
- Publisher:
- Public Library of ScienceCopyright Statement
- Country of Publication:
- United States
- Language:
- English
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