title: Impact of ABCB1 allelic variants on QTc interval prolongation.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 (ΔQTc) 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 ΔQTc 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.
authors.affiliation: Clinical Pharmacology Program, National Cancer Institute, Frederick, Maryland, USA.
authors.forename: Tristan M
authors.initials: TM
authors.lastname: Sissung
authors.forename: Erin R
authors.initials: ER
authors.lastname: Gardner
authors.forename: Richard L
authors.initials: RL
authors.lastname: Piekarz
authors.forename: Reuben
authors.initials: R
authors.lastname: Howden
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Chen
authors.forename: Sukyung
authors.initials: S
authors.lastname: Woo
authors.forename: Ryan
authors.initials: R
authors.lastname: Franke
authors.forename: James A
authors.initials: JA
authors.lastname: Clark
authors.forename: Laura
authors.initials: L
authors.lastname: Miller-DeGraff
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: David
authors.initials: D
authors.lastname: Venzon
authors.forename: David
authors.initials: D
authors.lastname: Liewehr
authors.forename: Steven R
authors.initials: SR
authors.lastname: Kleeberger
authors.forename: Susan E
authors.initials: SE
authors.lastname: Bates
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Price
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Rosing
authors.forename: Christopher
authors.initials: C
authors.lastname: Cabell
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D002460:Cell Line; D047630:Depsipeptides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D047630:Depsipeptides; C087123:romidepsin