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Updated: Jun 6, 2026

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
07:15

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation

Published on: January 16, 2019

Impact of ABCB1 allelic variants on QTc interval prolongation

Tristan M Sissung1, Erin R Gardner, Richard L Piekarz

  • 1Clinical Pharmacology Program, National Cancer Institute, Frederick, Maryland, USA.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|November 26, 2010
PubMed

Insights

The ABCB1 transporter limits drug buildup in the heart, reducing QT prolongation risk. Genetic variations in ABCB1 may predict a patient's response to certain drugs.

Area of Science:

  • Pharmacology
  • Cardiology
  • Genetics

Background:

  • The ABCB1 (P-glycoprotein) transporter is present in various physiological barriers.
  • Its role in a blood-heart barrier and potential impact on cardiotoxicity are not well understood.

Purpose of the Study:

  • To investigate the role of ABCB1 in limiting intracardiac drug concentrations.
  • To explore the relationship between ABCB1 activity, QT prolongation, and genetic variations.

Main Methods:

  • Studied romidepsin transport in cells with different ABCB1 variants.
  • Measured ABCB1 plasma and intracardiac concentrations in knockout and wild-type mice.
  • Assessed romidepsin-induced QT prolongation in mice.
  • Correlated ABCB1 genotypes with QTc prolongation in human subjects.

Main Results:

  • Mice lacking ABCB1 showed higher intracardiac romidepsin levels and increased QT prolongation.
  • Human subjects with genetic variants potentially increasing cardiac ABCB1 had reduced QT prolongation.

Conclusions:

  • This study provides the first evidence that ABCB1 limits drug exposure within the heart.
  • Common ABCB1 polymorphisms may serve as biomarkers for predicting QT prolongation risk with ABCB1 substrate drugs.
Abstract

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