Quantitative assessment of P-glycoprotein function in the rat blood-brain barrier by distribution volume of [11C]verapamil measured with PET

Neuroimage. 2003 Nov;20(3):1775-82. doi: 10.1016/s1053-8119(03)00405-1.


The blood-brain barrier (BBB) is a functional barrier that hampers the delivery of various drugs to the brain by its physicoanatomical properties and by the presence of ATP-driven drug efflux pumps, such as P-glycoprotein (P-gp). The aims of this study were (1) to study whether the distribution volume (DV) is useful for quantification of (labeled) P-gp substrate kinetics over the BBB and (2) to study how brain DV is affected by P-gp modulation. We measured the kinetics of the P-gp substrate [11C]verapamil (0.1 mg/kg) in rat brains using positron emission tomography (PET) and arterial blood sampling. Cyclosporin A (CsA) at 0, 10, 15, 25, 35, and 50 mg/kg of body weight was used as a P-gp modulator. The [11C]verapamil kinetics were very well described by DV, computed by noncompartmental Logan analysis. Logan analysis resulted in excellent fits of dynamic PET data, revealing the reversible behavior of [11C]verapamil and its associated DV. The DV in unmodulated rats was 0.65 ml/ml +/- 0.23 (mean +/- SD). After modulation with 10, 15, 25, 35, and 50 mg/kg of CsA, DV values increased to 0.82 +/- 0.06, 1.04 +/- 0.20, 2.85 +/- 0.51, 2.91 +/- 0.64, and 3.77 +/- 1.23, respectively. The [11C]Verapamil kinetics were saturable at modulation levels above 25 mg/kg of CsA. The data fitted well by a four-parameter Hill plot (R2 = 0.79). In conclusion, the DV of [11C]verapamil is a valid and potent tool to measure the kinetics of (labeled) P-gp substrates in vivo at the BBB. The brain DV of [11C]verapamil increases dose dependently by P-gp modulation. Quantitative insight into in vivo P-gp modulation may be a promising step toward assessment of P-gp substrate delivery to human brains.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology*
  • Animals
  • Blood-Brain Barrier / physiology*
  • Brain / diagnostic imaging*
  • Brain Chemistry / physiology*
  • Calcium Channel Blockers*
  • Carbon Radioisotopes
  • Cerebrovascular Circulation / physiology
  • Models, Neurological
  • Radiopharmaceuticals*
  • Rats
  • Rats, Wistar
  • Tomography, Emission-Computed
  • Verapamil*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Calcium Channel Blockers
  • Carbon Radioisotopes
  • Radiopharmaceuticals
  • Verapamil