TY - JOUR
T1 - Quantitative assessment of P-glycoprotein function in the rat blood-brain barrier by distribution volume of [11C]verapamil measured with PET
AU - Bart, Joost
AU - Willemsen, Antoon T.M.
AU - Groen, Harry J.M.
AU - Van Der Graaf, Winette T.A.
AU - Wegman, Theodora D.
AU - Vaalburg, Willem
AU - De Vries, Elisabeth G.E.
AU - Hendrikse, N. Harry
PY - 2003/1/1
Y1 - 2003/1/1
N2 - 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.
AB - 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.
KW - Blood-brain barrier
KW - Modeling
KW - P-glycoprotein
KW - Positron emission tomography
KW - [C]Verapamil
UR - http://www.scopus.com/inward/record.url?scp=0344121138&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/S1053-8119(03)00405-1
DO - https://doi.org/10.1016/S1053-8119(03)00405-1
M3 - Article
C2 - 14642487
SN - 1053-8119
VL - 20
SP - 1775
EP - 1782
JO - NEUROIMAGE
JF - NEUROIMAGE
IS - 3
ER -