MECHANISMS OF CARDIOTOXICITY OF ANTIPSYCHOTIC DRUGS

Summary

Principal Investigator: D A Flockhart
Abstract: DESCRIPTION: (Adapted from the Investigator's Abstract) This proposal involves a series of coordinated, translational studies designed to establish the mechanisms by which important antipsychotic drugs might bring about cardiac arrhythmias and sudden death. While a great deal of research over the past thirty years has resulted in the recent appearance of antipsychotic drugs that have reduced extra-pyramidal side-effects, a number of these novel agents have recently been shown to possess the ability to prolong the electrocardiac QT interval, and cause potentially lethal torsades-de-pointes arrhythmias that are reminiscent of older agents. Using antipsychotic drugs chosen for their wide clinical use, and potential cardiotoxicity the investigator propose to study potential pharmacodynamic and pharmacokinetic mechanisms that might expose vulnerable patients to the risk of these arrhythmias. The present study will have the following specific aims: 1) To test in vitro whether antipsychotic their metabolites or combinations of drug and metabolite modulate cardiac electrophysiology in isolated perfused heart using the characteristics of the action potential (AP), QT interval and early after depolarization (EAD) occurrence. To investigate whether any electrophysiologic changes noted are the result of specific cardiac Na, Ca, or K, channel activity in isolated ventricular cardiomyocytes and Purkinje cells, using currient patch clamp techniques. Since the investigators have preliminary data that indicate that haloperidol can slow cardiac repolarization in vitro, the focus of our studies in the first year will be on this widely-used drug and its metabolites. In subsequent years, the investigators will evaluate thioridazine, fluphenazine and loxapine. 2) To probe the cytochrome P450 isoforms responsible for metabolism of antipsychotic drugs or metabolites that the investigators find to be cardiotoxic. This information will allow assessment of pharmacogenetic and pharmacokinetic influences that might increase the concentration of these agents, and the risk of arrhythmia. The investigators will document the cytochrome P450 isoforms responsible for the metabolism of specific drugs using isolated human hepatic, intestinal and cardiac microsomal preparations, isoform-specific inhibitors and antibodies, and recombinant cytochrome P450 isoforms. 3) To determine if antipsychotic agents that are found to be potentially cardiotoxic in vitro have clinical electrocardiac effects at the doses routinely used in healthy volunteers. The investigator will document the relationship between the serum concentrations of these drugs and their electrocardiac pharmacodynamics. The results of these studies should allow physicians and researchers to more confidently predict patients at risk for lethal torsades-de-pointes arrhythmias while taking neuroleptic drugs, and to gain mechanistic insights that will allow the design of safer drugs in the future.
Funding Period: 1998-08-01 - 2004-07-31
more information: NIH RePORT

Top Publications

  1. ncbi The effects of tamoxifen and its metabolites on platelet function and release of reactive oxygen intermediates
    Olga Vitseva
    Boston University School of Medicine, 715 Albany St, W507, Boston, MA 02118, USA
    J Pharmacol Exp Ther 312:1144-50. 2005
  2. ncbi CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment
    Yan Jin
    Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    J Natl Cancer Inst 97:30-9. 2005
  3. pmc Possible interethnic differences in quinidine-induced QT prolongation between healthy Caucasian and Korean subjects
    Jae Gook Shin
    Department of Pharmacology and Pharmacogenomics Research Centre, Inje University College of Medicine, Busan, Korea
    Br J Clin Pharmacol 63:206-15. 2007
  4. ncbi Drug-drug interaction prediction: a Bayesian meta-analysis approach
    Lang Li
    Division of Biostatistics, Department of Medicine, Indiana University, IN, USA
    Stat Med 26:3700-21. 2007
  5. ncbi Estimating a positive false discovery rate for variable selection in pharmacogenetic studies
    Lang Li
    Department of Medicine, Division of Biostatistics, Indiana University, Indianapolis, Indiana 46202, USA
    J Biopharm Stat 17:883-902. 2007
  6. pmc A mixture model approach in gene-gene and gene-environmental interactions for binary phenotypes
    Lang Li
    Division of Biostatistics, Department of Medicine, Indiana University, Indianapolis, Indiana46202, USA
    J Biopharm Stat 18:1150-77. 2008
  7. pmc Estrogen receptor genotypes influence hot flash prevalence and composite score before and after tamoxifen therapy
    Yan Jin
    Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
    J Clin Oncol 26:5849-54. 2008

Scientific Experts

  • Lang Li
  • Yan Jin
  • David A Flockhart
  • Jae Gook Shin
  • Anne Nguyen
  • Suzanne Lemler
  • Daniel F Hayes
  • Vered Stearns
  • Anna Maria Storniolo
  • Jill Hayden
  • Olga Vitseva
  • Jason D Robarge
  • Anne Schott
  • Santosh Philips
  • Todd C Skaar
  • Million Arefayene
  • Dong Soo Kim
  • Kwang Hyun Cho
  • Doo Il Kim
  • Won Ku Kang
  • Kyung Ah Kim
  • Young Ran Yoon
  • Ji Hong Shon
  • Raymond L Woosley
  • Rebecca Blanchard
  • Jane E Freedman
  • Todd Skaar
  • Sonia Varghese
  • Zeruesenay Desta
  • Adjei Araba
  • Kyung Hoon Lee
  • James M Rae
  • Richard M Weinshilboum
  • Bryan Ward
  • Herbert Ho
  • Lynda Ullmer

Detail Information

Publications7

  1. ncbi The effects of tamoxifen and its metabolites on platelet function and release of reactive oxygen intermediates
    Olga Vitseva
    Boston University School of Medicine, 715 Albany St, W507, Boston, MA 02118, USA
    J Pharmacol Exp Ther 312:1144-50. 2005
    ..This results in modest changes in platelet function and seems to be consistent with previous oncological studies demonstrating tamoxifen-dependent increase in reactive oxygen species generation...
  2. ncbi CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment
    Yan Jin
    Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    J Natl Cancer Inst 97:30-9. 2005
    ....
  3. pmc Possible interethnic differences in quinidine-induced QT prolongation between healthy Caucasian and Korean subjects
    Jae Gook Shin
    Department of Pharmacology and Pharmacogenomics Research Centre, Inje University College of Medicine, Busan, Korea
    Br J Clin Pharmacol 63:206-15. 2007
    ....
  4. ncbi Drug-drug interaction prediction: a Bayesian meta-analysis approach
    Lang Li
    Division of Biostatistics, Department of Medicine, Indiana University, IN, USA
    Stat Med 26:3700-21. 2007
    ..Sensitivity analysis is conducted to justify prior distribution selections...
  5. ncbi Estimating a positive false discovery rate for variable selection in pharmacogenetic studies
    Lang Li
    Department of Medicine, Division of Biostatistics, Indiana University, Indianapolis, Indiana 46202, USA
    J Biopharm Stat 17:883-902. 2007
    ..Data analysis is illustrated with a pharmacogenetics example...
  6. pmc A mixture model approach in gene-gene and gene-environmental interactions for binary phenotypes
    Lang Li
    Division of Biostatistics, Department of Medicine, Indiana University, Indianapolis, Indiana46202, USA
    J Biopharm Stat 18:1150-77. 2008
    ..The mixture model approach has the highest recovery probability to recover the true partition in the simulation studies. Its applications are exemplified in interim data analyses for two cancer studies...
  7. pmc Estrogen receptor genotypes influence hot flash prevalence and composite score before and after tamoxifen therapy
    Yan Jin
    Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
    J Clin Oncol 26:5849-54. 2008
    ..We determined whether genetic polymorphisms in estrogen receptors (ESRs) alpha and beta (ESR1 and ESR2, respectively) are associated with tamoxifen-induced hot flashes...