Influence of functional haplotypes in the drug transporter gene ABCB1 on central nervous system drug distribution in humans

Clin Pharmacol Ther. 2005 Aug;78(2):182-90. doi: 10.1016/j.clpt.2005.04.011.


Background and 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.

Conclusion: No difference in the brain distribution of [(11)C]verapamil could be detected in healthy volunteers differing in ABCB1 haplotypes.

Publication types

  • Clinical Trial
  • Controlled Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Area Under Curve
  • Carbon Radioisotopes / administration & dosage
  • Carbon Radioisotopes / pharmacokinetics
  • Case-Control Studies
  • Central Nervous System / metabolism*
  • Central Nervous System Agents / administration & dosage
  • Central Nervous System Agents / pharmacokinetics*
  • Double-Blind Method
  • Genes, MDR*
  • Haplotypes
  • Humans
  • Injections, Intravenous
  • Male
  • Positron-Emission Tomography
  • Tissue Distribution
  • Verapamil / administration & dosage
  • Verapamil / pharmacokinetics*


  • Carbon Radioisotopes
  • Central Nervous System Agents
  • Verapamil