title: Quantitative assessment of P-glycoprotein function in the rat blood-brain barrier by distribution volume of [11C]verapamil measured with PET.
abstract: 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.
authors.affiliation: Department of Pulmonary Diseases, Groningen University Hospital, Groningen, The Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Bart
authors.forename: Antoon T M
authors.initials: AT
authors.lastname: Willemsen
authors.forename: Harry J M
authors.initials: HJ
authors.lastname: Groen
authors.forename: Winette T A
authors.initials: WT
authors.lastname: van der Graaf
authors.forename: Theodora D
authors.initials: TD
authors.lastname: Wegman
authors.forename: Willem
authors.initials: W
authors.lastname: Vaalburg
authors.forename: Elisabeth G E
authors.initials: EG
authors.lastname: de Vries
authors.forename: N Harry
authors.initials: NH
authors.lastname: Hendrikse
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000000981:diagnostic imaging*; D001923:Brain Chemistry / Q000502:physiology*; D002121:Calcium Channel Blockers; D002250:Carbon Radioisotopes; D002560:Cerebrovascular Circulation / Q000502:physiology; D008959:Models, Neurological; D019275:Radiopharmaceuticals; D051381:Rats; D017208:Rats, Wistar; D014055:Tomography, Emission-Computed; D014700:Verapamil
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002121:Calcium Channel Blockers; D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; D014700:Verapamil