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Effects of Antipsychotic Drugs on Ito, INa, Isus, IK1, and hERG: QT Prolongation, Structure Activity Relationship, and Network Analysis

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Purpose

To evaluate in vitro and computationally model the effects of selected antipsychotic drugs on several ionic currents that contribute to changes in the action potential in cardiac tissue.

Methods

Fourteen antipsychotic drugs or metabolites were examined to determine whether QT interval prolongation could be accounted for by an effect on one or more myocardial ion channels [Ito, INa, Isus, IK1, and human ether-a-go-go related gene (hERG)]. Using the patch clamp technique, drug effects on these human cardiac currents were tested.

Results

All molecules had little inhibitory effect on ion channels (blocking at concentrations >5 μM) other than hERG. A significant correlation was observed between the estimated hERG blockade and the increase in corrected QT for five of the antipsychotics. Molecular modeling identified hydrophobic features related to the interaction with hERG and correctly rank-ordered the test set molecules olanzapine and its metabolites. A network analysis of ligand and protein interactions around hERG using MetaCore™ (GeneGo Inc., St. Joseph, MI, USA) was used to visualize antipsychotics with affinity for this channel and their interactions with other proteins in this database.

Conclusion

The antipsychotics do not inhibit the ion channels Ito, INa, Isus, IK1 to any appreciable extent; however, blockade of hERG is a likely mechanism for the prolongation of the QT interval.

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Abbreviations

hERG:

human ether-a-go-go related gene

I K1 :

the inwardly rectifying potassium current

I Na :

sodium current

I sus :

sustained potassium current

I to :

transient outward potassium current

References

  1. S. H. Thomas (1994) ArticleTitleDrugs, QT interval abnormalities and ventricular arrhythmias Adverse Drug React. Toxicol. Rev. 13 77–102 Occurrence Handle7918900 Occurrence Handle1:STN:280:ByqD3c3ktl0%3D

    PubMed  CAS  Google Scholar 

  2. D. M. Barry H. Xu R. B. Schuessler J. M. Nerbonne (1998) ArticleTitleFunctional knockout of the transient outward current, long-QT syndrome, and cardiac remodeling in mice expressing a dominant-negative Kv4 alpha subunit Circ. Res. 83 560–567 Occurrence Handle9734479 Occurrence Handle1:CAS:528:DyaK1cXlvFCnsrw%3D

    PubMed  CAS  Google Scholar 

  3. M. C. Trudeau J. W. Warmke B. Ganetzky G. A. Robertson (1995) ArticleTitleHERG, a human inward rectifier in the voltage-gated potassium channel family Science 269 92–95 Occurrence Handle7604285 Occurrence Handle1:CAS:528:DyaK2MXmsl2ju7k%3D

    PubMed  CAS  Google Scholar 

  4. J. W. Warmke B. Ganetzky (1994) ArticleTitleA family of potassium channel genes related to eag in Drosophila and mammals Proc. Natl. Acad. Sci. USA 91 3438–3442 Occurrence Handle8159766 Occurrence Handle1:CAS:528:DyaK2cXksFWjt74%3D Occurrence Handle10.1073/pnas.91.8.3438

    Article  PubMed  CAS  Google Scholar 

  5. M. C. Sanguinetti C. Jiang M. E. Curran M. T. Keating (1995) ArticleTitleA mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel Cell 81 299–307 Occurrence Handle7736582 Occurrence Handle1:CAS:528:DyaK2MXlt1Kis7w%3D Occurrence Handle10.1016/0092-8674(95)90340-2

    Article  PubMed  CAS  Google Scholar 

  6. M. E. Curran I. Splawski K. W. Timothy G. M. Vincent E. D. Green M. T. Keating (1995) ArticleTitleA molecular basis for the cardiac arrhythmia: HERG mutations cause long QT syndrome Cell 80 795–803 Occurrence Handle7889573 Occurrence Handle1:CAS:528:DyaK2MXksVahsL4%3D Occurrence Handle10.1016/0092-8674(95)90358-5

    Article  PubMed  CAS  Google Scholar 

  7. H. Suessbrich R. Schonherr S. H. Heinemann B. Attali F. Lang A. E. Busch (1997) ArticleTitleThe inhibitory effect of the antipsychotic drug haloperidol on HERG potassium channels expressed in Xenopus oocytes Br. J. Pharmacol. 120 968–974 Occurrence Handle9138706 Occurrence Handle1:CAS:528:DyaK2sXhvFSrt78%3D

    PubMed  CAS  Google Scholar 

  8. A. Jeron G. F. Mitchell J. Zhou M. Murata B. London P. Buckett S. D. Wiviott G. Koren (2000) ArticleTitleInducible polymorphic ventricular tachyarrhythmias in a transgenic mouse model with a long Q–T phenotype Am. J. Physiol. Heart Circ. Physiol. 278 H1891–H1898 Occurrence Handle10843886 Occurrence Handle1:CAS:528:DC%2BD3cXks1ynu70%3D

    PubMed  CAS  Google Scholar 

  9. R. Welchand P. Chue (2000) ArticleTitleAntipsychotic agents and QT changes J. Psychiatry Neurosci. 25 154–160

    Google Scholar 

  10. D. Mehta S. Mehta J. Petit W. Shriner (1979) ArticleTitleCardiac arrhythmia and haloperidol Am. J. Psychiatr. 136 1468–1469 Occurrence Handle91324 Occurrence Handle1:STN:280:Bi%2BD2c%2FgtlM%3D

    PubMed  CAS  Google Scholar 

  11. S. Ekins W. J. Crumb R. D. Sarazan J. H. Wikel S. A. Wrighton (2002) ArticleTitleThree-dimensional quantitative structure–activity relationship for inhibition of human ether-a-go-go-related gene potassium channel J. Pharmacol. Exp. Ther. 301 427–434 Occurrence Handle11961040 Occurrence Handle1:CAS:528:DC%2BD38XjtlKjur0%3D Occurrence Handle10.1124/jpet.301.2.427

    Article  PubMed  CAS  Google Scholar 

  12. W. J. Crumb SuffixJr. J. D. Pigott C. W. Clarkson (1995) ArticleTitleComparison of Ito in young and adult human atrial myocytes: evidence for developmental changes Am. J. Physiol. 268 H1335–H1342 Occurrence Handle7900886 Occurrence Handle1:CAS:528:DyaK2MXkslKrsbw%3D

    PubMed  CAS  Google Scholar 

  13. O. P. Hamill A. Marty E. Neher B. Sakmann F. J. Sigworth (1981) ArticleTitleImproved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches Pflugers Arch. 391 85–100 Occurrence Handle6270629 Occurrence Handle1:STN:280:Bi2D3sjhvVw%3D Occurrence Handle10.1007/BF00656997

    Article  PubMed  CAS  Google Scholar 

  14. S. Ekins A. Bugrim Y. Nikolsky T. Nikolskaya (2005) Systems biology: applications in drug discovery S. C. Gad (Eds) Drug Discovery Handbook Wiley New York 123–183

    Google Scholar 

  15. S. Ekins E. Kirillov E. A. Rakhmatulin T. Nikolskaya (2005) ArticleTitleA Novel Method for Visualizing Nuclear Hormone Receptor Networks Relevant to Drug Metabolism Drug Metab. Dispos. 33 474–481 Occurrence Handle15608136 Occurrence Handle1:CAS:528:DC%2BD2MXisFSgt7w%3D Occurrence Handle10.1124/dmd.104.002717

    Article  PubMed  CAS  Google Scholar 

  16. E. P. Harrigan J. J. Miceli R. Anziano E. Watsky K. R. Reeves N. R. Cutler J. Sramek T. Shiovitz M. Middle (2004) ArticleTitleA randomized evaluation of the effects of six antipsychotic agents on QTc, in the absence and presence of metabolic inhibition J. Clin. Psychopharmacol. 24 62–69 Occurrence Handle14709949 Occurrence Handle1:CAS:528:DC%2BD2cXhtlCmuw%3D%3D Occurrence Handle10.1097/01.jcp.0000104913.75206.62

    Article  PubMed  CAS  Google Scholar 

  17. Pfizer briefing document for Zeldox Capsules (Ziprasidone HCl). July 19, 2000.

  18. K. Titier M. Canal E. Deridet A. Abouelfath S. Gromb M. Molimard N. Moore (2004) ArticleTitleDetermination of myocardium to plasma concentration ratios of five antipsychotic drugs: comparison with their ability to induce arrhythmia and sudden death in clinical practice Toxicol. Appl. Pharmacol. 199 52–60 Occurrence Handle15289090 Occurrence Handle1:CAS:528:DC%2BD2cXmt1Khtrs%3D Occurrence Handle10.1016/j.taap.2004.03.016

    Article  PubMed  CAS  Google Scholar 

  19. M. Malik (2001) ArticleTitleProblems of heart rate correction in assessment of drug-induced QT interval prolongation J. Cardiovasc. Electrophysiol. 12 411–420 Occurrence Handle11332559 Occurrence Handle1:STN:280:DC%2BD3MrgsFSrtA%3D%3D Occurrence Handle10.1046/j.1540-8167.2001.00411.x

    Article  PubMed  CAS  Google Scholar 

  20. M. Malik A. J. Camm (2001) ArticleTitleEvaluation of drug-induced QT interval prolongation: implications for drug approval and labelling Drug Safety 24 323–351 Occurrence Handle11419561 Occurrence Handle1:CAS:528:DC%2BD3MXjvVakt7g%3D Occurrence Handle10.2165/00002018-200124050-00001

    Article  PubMed  CAS  Google Scholar 

  21. R. R. Shah (2002) ArticleTitleThe significance of QT interval in drug development Br. J. Clin. Pharmacol. 54 188–202 Occurrence Handle12207642 Occurrence Handle1:CAS:528:DC%2BD38XnvVWis7o%3D Occurrence Handle10.1046/j.1365-2125.2002.01627.x

    Article  PubMed  CAS  Google Scholar 

  22. H. J. Witchel J. C. Hancox D. J. Nutt (2003) ArticleTitlePsychotropic drugs, cardiac arrhythmia, and sudden death J. Clin. Psychopharmacol. 23 58–77 Occurrence Handle12544377 Occurrence Handle1:CAS:528:DC%2BD3sXmsVSmtg%3D%3D Occurrence Handle10.1097/00004714-200302000-00010

    Article  PubMed  CAS  Google Scholar 

  23. R. Webster D. Leishman D. Walker (2002) ArticleTitleTowards a drug concentration effect relationship for QT prolongation and torsades de pointes Curr. Opin. Drug Discov. Dev. 5 116–126 Occurrence Handle1:CAS:528:DC%2BD38XitF2gsro%3D

    CAS  Google Scholar 

  24. W. Crumband I. Cavero (1999) ArticleTitleQT interval prolongation by non-cardiovascular drugs: issues and solutions for novel drug development PSST 2 270–280

    Google Scholar 

  25. S. Zhang Z. Zhou Q. Gong J. C. Makielski C. T. January (1999) ArticleTitleMechanism of block and identification of the verapamil binding domain to HERG potassium channels Circ. Res. 84 989–998 Occurrence Handle10325236 Occurrence Handle1:CAS:528:DyaK1MXjtFCjtr0%3D

    PubMed  CAS  Google Scholar 

  26. J. Kang X. L. Chen H. Wang J. Ji W. Reynolds S. Lim J. Hendrix D. Rampe (2004) ArticleTitleCardiac ion channel effects of tolterodine J. Pharmacol. Exp. Ther. 308 935–940 Occurrence Handle14711935 Occurrence Handle1:CAS:528:DC%2BD2cXhvVWntLk%3D Occurrence Handle10.1124/jpet.103.062182

    Article  PubMed  CAS  Google Scholar 

  27. M. B. Thomsen P. G. Volders M. Stengl R. L. Spatjens J. D. Beekman U. Bischoff M. A. Kall K. Frederiksen J. Matz M. A. Vos (2003) ArticleTitleElectrophysiological safety of sertindole in dogs with normal and remodeled hearts J. Pharmacol. Exp. Ther. 307 776–784 Occurrence Handle12966159 Occurrence Handle1:CAS:528:DC%2BD3sXos1ShsLs%3D Occurrence Handle10.1124/jpet.103.052753

    Article  PubMed  CAS  Google Scholar 

  28. F. M. Belpaire F. A. Vanderheeren M. G. Bogaert (1975) ArticleTitleBinding of thioridazine and some of its metabolites to human serum protein and human albumin Arzneim. Forsch. 25 1969–1971 Occurrence Handle1:CAS:528:DyaE28Xotl2ktw%3D%3D

    CAS  Google Scholar 

  29. J. T. Niemann J. S. Stapczynski R. J. Rothstein M. M. Laks (1981) ArticleTitleCardiac conduction and rhythm disturbances following suicidal ingestion of mesoridazine Ann. Emerg. Med. 10 585–588 Occurrence Handle7316263 Occurrence Handle1:STN:280:Bi2D1cbltFY%3D Occurrence Handle10.1016/S0196-0644(81)80198-9

    Article  PubMed  CAS  Google Scholar 

  30. S. A. Fayer (1986) ArticleTitleTorsades de pointes ventricular tachyarrhythmia associated with haloperidol J. Clin. Psychopharmacol. 6 375–376 Occurrence Handle3805334 Occurrence Handle1:STN:280:BiiC3cbptVY%3D

    PubMed  CAS  Google Scholar 

  31. I. Paakkari (2002) ArticleTitleCardiotoxicity of new antihistamines and cisapride Toxicol. Lett. 127 279–284 Occurrence Handle12052668 Occurrence Handle1:CAS:528:DC%2BD38XjtFKju7s%3D Occurrence Handle10.1016/S0378-4274(01)00510-0

    Article  PubMed  CAS  Google Scholar 

  32. H. A. Nasrallah (1978) ArticleTitleFactors influencing phenothiazine-induced ECG changes Am. J. Psychiatr. 135 118–119 Occurrence Handle22250 Occurrence Handle1:STN:280:CSeD2MfksFM%3D

    PubMed  CAS  Google Scholar 

  33. N. A. Aunsholt (1989) ArticleTitleProlonged Q–T interval and hypokalemia caused by haloperidol Acta Psychiatr. Scand. 79 411–412 Occurrence Handle2735214 Occurrence Handle1:STN:280:BiaB1cvpsVM%3D

    PubMed  CAS  Google Scholar 

  34. M. N. Siddiqui H. Zafar R. Alvi M. Ahmed (1998) ArticleTitleHypomagnesaemia in postoperative patients: an important contributing factor in postoperative mortality Int. J. Clin. Pract. 52 265–267 Occurrence Handle9744153 Occurrence Handle1:STN:280:DyaK1cvhs1yitA%3D%3D

    PubMed  CAS  Google Scholar 

  35. S. Ekins P. W. Swaan (2004) ArticleTitleDevelopment of computational models for enzymes, transporters, channels and receptors relevant to ADME/TOX Rev. Comp. Chem. 20 333–415 Occurrence Handle1:CAS:528:DC%2BD2MXhvFOisr0%3D Occurrence Handle10.1002/0471678856.ch6

    Article  CAS  Google Scholar 

  36. J. S. Mitcheson J. Chen M. Lin C. Culberson M. C. Sanguinetti (2000) ArticleTitleA structural basis for drug-induced long QT syndrome Proc. Natl. Acad. Sci. U. S. A. 97 12329–12333 Occurrence Handle11005845 Occurrence Handle1:CAS:528:DC%2BD3cXnvVSnsro%3D Occurrence Handle10.1073/pnas.210244497

    Article  PubMed  CAS  Google Scholar 

  37. S. Ekins (2004) ArticleTitlePredicting undesirable drug interactions with promiscuous proteins in silico Drug Discov. Today 9 276–285 Occurrence Handle15003246 Occurrence Handle1:CAS:528:DC%2BD2cXhslelsLc%3D Occurrence Handle10.1016/S1359-6446(03)03008-3

    Article  PubMed  CAS  Google Scholar 

  38. H. Li J. Sutter R. Hoffman (2000) HypoGen: an automated system for generating 3D predictive pharmacophore models O. F. Guner (Eds) Pharmacophore Perception, Development, and Use in Drug Design IUL San Diego 173–189

    Google Scholar 

  39. J. S. Mitcheson (2003) ArticleTitleDrug binding to HERG channels: evidence for a ‘non-aromatic’ binding site for fluvoxamine Br. J. Pharmacol. 139 883–884 Occurrence Handle12839860 Occurrence Handle1:CAS:528:DC%2BD3sXlvVCjurg%3D Occurrence Handle10.1038/sj.bjp.0705336

    Article  PubMed  CAS  Google Scholar 

  40. I. Huys C. Q. Xu C. Z. Wang H. Vacher M. F. Martin-Eauclaire C. W. Chi J. Tytgat (2004) ArticleTitleBmTx3, a scorpion toxin with two putative functional faces separately active on A-type K+ and HERG currents Biochem. J. 378 745–752 Occurrence Handle14599291 Occurrence Handle1:CAS:528:DC%2BD2cXisVykt78%3D Occurrence Handle10.1042/BJ20031324

    Article  PubMed  CAS  Google Scholar 

  41. Y. V. Korolkova E. V. Bocharov K. Angelo I. V. Maslennikov O. V. Grinenko A. V. Lipkin E. D. Nosyreva K. A. Pluzhnikov S. P. Olesen A. S. Areseniev E. V. Grishin (2002) ArticleTitleNew binding site on common molecular scaffold provides HERG channel specificity of scorpion toxin BeKm-1 J. Biol. Chem. 277 43104–43109 Occurrence Handle12151390 Occurrence Handle1:CAS:528:DC%2BD38Xos1enu7c%3D Occurrence Handle10.1074/jbc.M204083200

    Article  PubMed  CAS  Google Scholar 

  42. A. M. Torres P. Bansal P. F. Alewood J. A. Bursill P. W. Kuchel J. I. Vandenberg (2003) ArticleTitleSolution structure of CnErg1 (Ergtoxin), a HERG specific scorpion toxin FEBS Lett. 539 138–142 Occurrence Handle12650941 Occurrence Handle1:CAS:528:DC%2BD3sXitFamsLc%3D Occurrence Handle10.1016/S0014-5793(03)00216-3

    Article  PubMed  CAS  Google Scholar 

  43. S. Ekins (2004) ArticleTitlePredicting undesirable drug interactions with promiscuous proteins in silico Drug Discov. Today 9 276–285 Occurrence Handle15003246 Occurrence Handle1:CAS:528:DC%2BD2cXhslelsLc%3D Occurrence Handle10.1016/S1359-6446(03)03008-3

    Article  PubMed  CAS  Google Scholar 

  44. A. Luca ParticleDe S. Talon M. Bellis ParticleDe J. F. Desaphy G. Lentini F. Corbo A. Scilimati C. Franchini V. Tortorella D. C. Camerino (2003) ArticleTitleOptimal requirements for high affinity and use-dependent block of skeletal muscle sodium channel by N-benzyl analogs of tocainide-like compounds Mol. Pharmacol. 64 932–945 Occurrence Handle14500750 Occurrence Handle10.1124/mol.64.4.932

    Article  PubMed  Google Scholar 

  45. L. S. Goodman L. E. Limbard P. B. Molinoff R. W. Ruddon A. G. Gilman (2003) Goodman & Gilman’s the Pharmacological Basis of Therapeutics McGraw-Hill New York

    Google Scholar 

  46. Physicians’ Desk Reference (PDR), Medical Economics, Thompson Healthcare, Montvale, NJ, 2004.

  47. E. C. Dinovo H. Pollak L. A. Gottschalk (1984) ArticleTitlePartitioning of thioridazine and mesoridazine in human blood fractions Methods Find. Exp. Clin. Pharmacol. 6 143–146 Occurrence Handle6748818 Occurrence Handle1:CAS:528:DyaL2cXktlaku7g%3D

    PubMed  CAS  Google Scholar 

  48. G. Nyberg R. Axelsson E. Martensson (1978) ArticleTitleBinding of thioridazine and thioridazine metabolites to serum proteins in psychiatric patients Eur. J. Clin. Pharmacol. 14 341–350 Occurrence Handle32045 Occurrence Handle1:CAS:528:DyaE1MXhtFCktbg%3D Occurrence Handle10.1007/BF00611904

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We acknowledge the many scientists whose work we were unable to quote due to the limitations of space.

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Author notes

  1. Sean Ekins

    Present address: GeneGo, Inc., 500 Renaissance Drive, Suite 106, St. Joseph, Michigan 49085, USA, GeneGo Inc., 601 Runnymede Ave., Jenkintown, PA, 19046, USA

  2. R. Dustan Sarazan

    Present address: Covance Laboratories Inc., 3301 Kinsman Boulevard, Madison, Wisconsin, 53704, USA

  3. James H. Wikel

    Present address: Coalesix Inc., 10 Fawcett Street, Cambridge, Massachusetts, 02138, USA

Authors and Affiliations

  1. Department of Pediatrics (Cardiology), Tulane University School of Medicine, New Orleans, Lousiana, USA

    William J. Crumb Jr.

  2. Lilly Research Laboratories, Elli Lilly and Co., Indianapolis, Indiana, USA

    Sean Ekins, R. Dustan Sarazan, James H. Wikel, Steven A. Wrighton, Christopher Carlson & Charles M. Beasley Jr.

  3. Lilly Corporate Center, #1730, Indianapolis, Indiana, 46285, USA

    Charles M. Beasley Jr.

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  1. William J. Crumb Jr.
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Correspondence to Sean Ekins.

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Crumb, W.J., Ekins, S., Sarazan, R.D. et al. Effects of Antipsychotic Drugs on Ito, INa, Isus, IK1, and hERG: QT Prolongation, Structure Activity Relationship, and Network Analysis. Pharm Res 23, 1133–1143 (2006). https://doi.org/10.1007/s11095-006-0070-7

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