Rosuvastatin Blocks hERG Current and Prolongs Cardiac Repolarization

• Published in: Journal of pharmaceutical sciences Vol. 101; no. 2; pp. 868 - 878
• Main Authors: Plante, Isabelle, Vigneault, Patrick, Drolet, Benoît, Turgeon, Jacques
• Format: Journal Article
• Language: English
• Published: Hoboken Elsevier Inc 01.02.2012; Wiley Subscription Services, Inc., A Wiley Company; Wiley; American Pharmaceutical Association; Elsevier Limited
• Subjects: Action Potentials - drug effects; Animals; Biological and medical sciences; cardiac repolarization; Cell Line; drugs; Fluorobenzenes - pharmacology; General pharmacology; Guinea Pigs; Heart - drug effects; Heart - physiology; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; In Vitro Techniques; long QT syndrome; Male; Medical sciences; Mutagenesis, Site-Directed; Patch-Clamp Techniques; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; potassium current; Pyrimidines - pharmacology; Rosuvastatin Calcium; Sulfonamides - pharmacology; torsades de pointes; cardiac repolarization; torsades de pointes; long QT syndrome; drugs; potassium current; Heart; Repolarization; Arrhythmia; Cardiovascular disease; Rosuvastatin; Hypocholesterolemic agent; Inorganic element; Heart block; Heart disease; HMG-CoA reductase inhibitor; Torsades de pointes; Drug; Pharmaceutical technology; Enzyme; Prolonged QT interval; Enzyme inhibitor; Statin derivative; Conduction disorder; Excitability disorder; Hydroxymethylglutaryl-CoA reductase; Oxidoreductases; Potassium; Block copolymer; Antilipemic agent; Prolonged
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.22809

Blocking of the potassium current IKr [human ether-a-go-go related gene (hERG)] is generally associated with an increased risk of long QT syndrome (LQTS). The 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor, rosuvastatin, is a methanesulfonamide derivative, which shows structural similarities with several IKr blockers. Hence, we assessed the effects of rosuvastatin on cardiac repolarization by using in vitro, ex vivo, and in vivo models. Patch clamp experiments on hERG-transfected human embryonic kidney (HEK) 293 cells established the potency of rosuvastatin to block hERG [half maximal inhibitory concentration (IC50) = 195nM]. We showed in isolated guinea pig hearts that 195nM rosuvastatin prolonged (basic cycle length of 250ms; p < 0.05) the monophasic action potential duration at 90% repolarization (MAPD90) by 11 ± 1ms. Finally, rosuvastatin (10mg/kg, intraperitoneal) prolonged corrected QT interval (QTc) in conscious and unrestrained guinea pigs from 201 ± 1 to 210 ± 2ms (p < 0.05). Thus, rosuvastatin blocks IKr and prolongs cardiac repolarization. In additional experiments, we also show that hERG blockade in HEK 293 cells was modulated by coexpression of efflux [breast cancer resistance protein (BCRP), multidrug resistance gene (MDR1)] and influx [organic anion transporting polypeptide (OATP) 2B1] transporters involved in the disposition and cardiac distribution of the drug. Genetic polymorphisms observed for BCRP, MDR1, and OATP2B1, and IC50 determined for hERG blocking lead us to propose that some patients may be at risk of rosuvastatin-induced LQTS. © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association.