Mechanisms of QT prolongation by buprenorphine cannot be explained by direct hERG channel block

被引：24

作者：

Tran, Phu N. ^{[1
,2
]}

Sheng, Jiansong ^{[1
,3
]}

Randolph, Aaron L. ^{[1
]}

Baron, Claudia Alvarez ^{[1
]}

Thiebaud, Nicolas ^{[1
,4
]}

Ren, Ming ^{[1
]}

Wu, Min ^{[1
,2
]}

Johannesen, Lars ^{[5
]}

Volpe, Donna A. ^{[1
]}

Patel, Dakshesh ^{[6
,7
]}

Blinova, Ksenia ^{[6
]}

Strauss, David G. ^{[1
]}

Wu, Wendy W. ^{[1
]}

机构：

[1] US FDA, Div Appl Regulatory Sci, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA

[2] US FDA, Div Immunol & Hematol Devices, Ctr Devices & Radiol Hlth, Silver Spring, MD USA

[3] CiPALab, Gaithersburg, MD USA

[4] Vertex Pharmaceut Europe Ltd, Abingdon, Oxon, England

[5] US FDA, Div Cardiol & Nephrol, Off Cardiol Hematol Endocrinol & Nephrol, Off New Drugs,Ctr Drug Evaluat & Res, Silver Spring, MD USA

[6] US FDA, Div Biomed Phys, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA

[7] Harvard Med Sch, Cardiovasc Res Ctr, Massachusetts Gen Hosp, Boston, MA 02115 USA

来源：

PLOS ONE | 2020年 / 15卷 / 11期

关键词：

MU-OPIOID-RECEPTOR; CELL-DERIVED CARDIOMYOCYTES; ANESTHETIC-LIKE INHIBITION; CARDIAC REPOLARIZATION; INTERVAL PROLONGATION; IN-VITRO; METHADONE; NALOXONE; AGONIST; BINDING;

D O I：

10.1371/journal.pone.0241362

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Buprenorphine is a mu-opioid receptor (MOR) partial agonist used to manage pain and addiction. QT(C) 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(R). Because QT(C) 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 QT(C) prolongation and TdP are most commonly caused by acute inhibition of hERG current (I-hERG) that contribute to the repolarizing phase of the ventricular action potentials (APs). Concomitant inhibition of inward late Na+ (I-NaL) and/or L-type Ca2+ (I-CaL) 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 QT(C) prolongation and high TdP risk, and naltrexone and naloxone, two opioid receptor antagonists, were also studied. Whole cell recordings were performed at 37 degrees C on cells stably expressing hERG, Ca(V)1.2, and Na(V)1.5 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 I-hERG, I-CaL, I-NaL, and peak Na+ current (I-NaP) at clinically relevant concentrations. In contrast, methadone inhibited I-hERG, I-CaL, and I-NaL. 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 QT(C) 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 QT(C) prolongation not mediated by acute hERG channel block warrants further study.

引用

页数：26

共 74 条

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