{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T12:08:58Z","timestamp":1789474138931,"version":"build-2803163510"},"reference-count":96,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T00:00:00Z","timestamp":1693958400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Loperamide has been a safe and effective treatment for diarrhea for many years. However, many cases of cardiotoxicity with intentional abuse of loperamide ingestion have recently been reported. We evaluated loperamide in in vitro and in vivo cardiac safety models to understand the mechanisms for this cardiotoxicity. Loperamide slowed conduction (QRS-duration) starting at 0.3 \u00b5M [~1200-fold (\u00d7) its human Free Therapeutic Plasma Concentration; FTPC] and reduced the QT-interval and caused cardiac arrhythmias starting at 3 \u00b5M (~12,000\u00d7 FTPC) in an isolated rabbit ventricular-wedge model. Loperamide also slowed conduction and elicited Type II\/III A-V block in anesthetized guinea pigs at overdose exposures of 879\u00d7 and 3802\u00d7 FTPC. In ion-channel studies, loperamide inhibited hERG (IKr), INa, and ICa currents with IC50 values of 0.390 \u00b5M, 0.526 \u00b5M, and 4.091 \u00b5M, respectively (i.e., &gt;1560\u00d7 FTPC). Additionally, in silico trials in human ventricular action potential models based on these IC50s confirmed that loperamide has large safety margins at therapeutic exposures (\u2264600\u00d7 FTPC) and confirmed repolarization abnormalities in the case of extreme doses of loperamide. The studies confirmed the large safety margin for the therapeutic use of loperamide but revealed that at the extreme exposure levels observed in human overdose, loperamide can cause a combination of conduction slowing and alterations in repolarization time, resulting in cardiac proarrhythmia. Loperamide\u2019s inhibition of the INa channel and hERG-mediated IKr are the most likely basis for this cardiac electrophysiological toxicity at overdose exposures. The cardiac toxic effects of loperamide at the overdoses could be aggravated by co-medication with other drug(s) causing ion channel inhibition.<\/jats:p>","DOI":"10.3390\/biom13091355","type":"journal-article","created":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T10:07:37Z","timestamp":1693994857000},"page":"1355","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The Potential Mechanisms behind Loperamide-Induced Cardiac Arrhythmias Associated with Human Abuse and Extreme Overdose"],"prefix":"10.3390","volume":"13","author":[{"given":"Hua Rong","family":"Lu","sequence":"first","affiliation":[{"name":"Global Safety Pharmacology, Janssen Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce P.","family":"Damiano","sequence":"additional","affiliation":[{"name":"Global Safety Pharmacology, Janssen Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9159-9554","authenticated-orcid":false,"given":"Mohamed","family":"Kreir","sequence":"additional","affiliation":[{"name":"Global Safety Pharmacology, Janssen Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jutta","family":"Rohrbacher","sequence":"additional","affiliation":[{"name":"Global Safety Pharmacology, Janssen Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henk","family":"van der Linde","sequence":"additional","affiliation":[{"name":"Global Safety Pharmacology, Janssen Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamerlan","family":"Saidov","sequence":"additional","affiliation":[{"name":"Global Safety Pharmacology, Janssen Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ard","family":"Teisman","sequence":"additional","affiliation":[{"name":"Global Safety Pharmacology, Janssen Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Gallacher","sequence":"additional","affiliation":[{"name":"Global Safety Pharmacology, Janssen Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,6]]},"reference":[{"key":"ref_1","first-page":"494","article-title":"Loperamide (ADL 2-1294), an opioid antihyperalgesic agent with peripheral selectivity","volume":"289","author":"Burgos","year":"1999","journal-title":"J. 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