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Impact of ABCB1 Allelic Variants on QTc Interval Prolongation

  1. Author:
    Sissung, T. M.
    Gardner, E. R.
    Piekarz, R. L.
    Howden, R.
    Chen, X. H.
    Woo, S.
    Franke, R.
    Clark, J. A.
    Miller-DeGraff, L.
    Steinberg, S. M.
    Venzon, D.
    Liewehr, D.
    Kleeberger, S. R.
    Bates, S. E.
    Price, D. K.
    Rosing, D. R.
    Cabell, C.
    Sparreboom, A.
    Figg, W. D.

  2. Author Address

    [Figg, William D.] NCI, Clin Pharmacol Program, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Sissung, Tristan M.; Chen, Xiaohong; Woo, Sukyung; Figg, William D.] NCI, Clin Pharmacol Program, Frederick, MD 21701 USA. [Gardner, Erin R.] NCI, SAIC Frederick, Frederick, MD 21701 USA. [Howden, Reuben; Clark, James A.; Miller-DeGraff, Laura; Kleeberger, Steven R.] NIEHS, Lab Resp Biol, Durham, NC USA. [Franke, Ryan; Sparreboom, Alex] St Jude Childrens Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA. [Steinberg, Seth M.; Venzon, David; Liewehr, David] NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. [Price, Douglas K.; Figg, William D.] NCI, Mol Pharmacol Sect, Ctr Canc Res, Bethesda, MD 20892 USA. [Rosing, Douglas R.] Natl Heart Lung & Blood Inst, Cardiovasc Branch, Bethesda, MD USA. [Cabell, Christopher] Quintiles Transnatl Corp, Res Triangle Pk, NC USA.;Figg, WD, NCI, Clin Pharmacol Program, Med Oncol Branch, Ctr Canc Res, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA.;wdfigg@helix.nih.gov
    1. Year: 2011
    2. Date: Feb
  2. Journal: Clinical Cancer Research
    1. 17
    2. 4
    3. Pages: 937-946
  4. Type of Article: Article
  5. ISSN: 1078-0432
  1. Abstract:

    Purpose: Although the ABCB1 (P-glycoprotein) drug transporter is a constituent of several blood-tissue barriers (i.e., blood-brain and blood-nerve), its participation in a putative blood-heart barrier has been poorly explored. ABCB1 could decrease the intracardiac concentrations of drugs that cause QT prolongation and cardiotoxicity. Experimental Design: ABCB1-related romidepsin transport kinetics were explored in LLC-PK1 cells transfected with different ABCB1 genetic variants. ABCB1 plasma and intracardiac concentrations were determined in Abcb1a/1b (-/-) mice and wild-type FVB controls. These same mice were used to evaluate romidepsin-induced heart rate-corrected QT interval (QTc) prolongation over time. Finally, a cohort of 83 individuals with available QTcB and ABCB1 genotyping data were used to compare allelic variation in ABCB1 versus QTc-prolongation phenotype. Results: Here, we show that mice lacking the ABCB1-type P-glycoprotein have higher intracardiac concentrations of a model ABCB1 substrate, romidepsin, that correspond to changes in QT prolongation from baseline (Delta QTc) over time. Consistent with this observation, we also show that patients carrying genetic variants that could raise ABCB1 expression in the cardiac endothelium have lower Delta QTc following a single dose of romidepsin. Conclusions: To our knowledge, this is the first evidence that Abcb1-type P-glycoprotein can limit intracardiac exposure to a drug that mediates QT prolongation and suggests that certain commonly inherited polymorphisms in ABCB1 may serve as markers for QT prolongation following the administration of ABCB1-substrate drugs. Clin Cancer Res; 17(4); 937-46. (C) 2010 AACR.

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External Sources

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  2. DOI: 10.1158/1078-0432.ccr-10-0925
  3. View record in Web of Science®
  4. WOS: 000287913200033

Library Notes

  1. Fiscal Year: FY2010-2011
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