title: Influence of functional haplotypes in the drug transporter gene ABCB1 on central nervous system drug distribution in humans.
abstract: OBJECTIVE
  Single nucleotide polymorphisms in the human multidrug-resistance gene ABCB1 have been reported to be associated with altered expression and function of P-glycoprotein, an efflux transporter, expressed at the blood-brain barrier. To test whether certain ABCB1 haplotypes contribute to interindividual differences in central nervous system drug distribution, brain distribution of a model P-glycoprotein substrate, the calcium channel inhibitor verapamil, was measured by positron emission tomography (PET) in 2 groups of healthy volunteers.
  
  
  METHODS
  Ten homozygous carriers (cases) of the TTT haplotype (3435T, 1236T, and 2677T) and 10 controls homozygous for the wild-type CGC haplotype (3435C, 2677G, and 1236C) were administered a mean intravenous bolus of 412 +/- 114 MBq carbon 11-labeled verapamil containing less than 15 nmol of unlabeled verapamil. PET imaging of brain tissue and venous blood sampling were performed for 1 hour after dosing.
  
  
  RESULTS
  As a measure of brain penetration, the ratio of PET area under the time-radioactivity curve (AUC) to plasma AUC was calculated from time-radioactivity curves, with a mean ratio of 1.1 +/- 0.3 (SD) (95% confidence interval, 0.9-1.3) for cases and 1.1 +/- 0.2 (95% confidence interval, 0.9-1.2) for controls, respectively (P = .96). Mean brain AUC values were 31.2 +/- 3.9 and 35.7 +/- 5.7 for the TTT and CGC haplotype, respectively (P = .11). Plasma AUCs were not significantly different.
  
  
  CONCLUSIONS
  No difference in the brain distribution of [(11)C]verapamil could be detected in healthy volunteers differing in ABCB1 haplotypes.
authors.affiliation: Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, Institute of Medical and Chemical Laboratory Diagnostics, Vienna, Austria. marin.brunner@meduniwien.ac.at
authors.forename: Martin
authors.initials: M
authors.lastname: Brunner
authors.forename: Oliver
authors.initials: O
authors.lastname: Langer
authors.forename: Raute
authors.initials: R
authors.lastname: Sunder-Plassmann
authors.forename: Georg
authors.initials: G
authors.lastname: Dobrozemsky
authors.forename: Ulrich
authors.initials: U
authors.lastname: Müller
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wadsak
authors.forename: Andreas
authors.initials: A
authors.lastname: Krcal
authors.forename: Rudolf
authors.initials: R
authors.lastname: Karch
authors.forename: Christine
authors.initials: C
authors.lastname: Mannhalter
authors.forename: Robert
authors.initials: R
authors.lastname: Dudczak
authors.forename: Kurt
authors.initials: K
authors.lastname: Kletter
authors.forename: Ilka
authors.initials: I
authors.lastname: Steiner
authors.forename: Christoph
authors.initials: C
authors.lastname: Baumgartner
authors.forename: Markus
authors.initials: M
authors.lastname: Müller
mesh_terms: D000328:Adult; D019540:Area Under Curve; D002250:Carbon Radioisotopes / Q000008:administration & dosage / Q000493:pharmacokinetics; D016022:Case-Control Studies; D002490:Central Nervous System / Q000378:metabolism*; D002491:Central Nervous System Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D019450:Genes, MDR; D006239:Haplotypes; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D049268:Positron-Emission Tomography; D014018:Tissue Distribution; D014700:Verapamil / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D002250:Carbon Radioisotopes; D002491:Central Nervous System Agents; D014700:Verapamil