title: [¹¹C]befloxatone brain kinetics is not influenced by Bcrp function at the blood-brain barrier: a PET study using Bcrp TGEM knockout rats.
abstract: Knockout (KO) animals are useful tools with which to assess the interplay between P-glycoprotein (P-gp; Abcb1) and the breast cancer resistance protein (Bcrp, Abcg2), two major ABC-transporters expressed at the blood-brain barrier (BBB). However, one major drawback of such deficient models is the possible involvement of compensation between transporters. In the present study, P-gp and Bcrp distribution in the brain as well as P-gp expression levels at the BBB were compared between the Bcrp TGEM KO rat model and the wild-type (WT) strain. Therefore, we used confocal microscopy of brain slices and western blot analysis of the isolated brain microvessels forming the BBB. This deficient rat model was used to assess the influence of Bcrp on the brain and peripheral kinetics of its substrate [(11)C]befloxatone using positron emission tomography (PET). The influence of additional P-gp inhibition was tested using elacridar (GF120918) 2 mg/kg in Bcrp KO rats. The distribution pattern of P-gp in the brain as well as P-gp expression levels at the BBB was similar in Bcrp-deficient and WT rats. Brain and peripheral kinetics of [(11)C]befloxatone were not influenced by the lack of Bcrp. Neither was the brain uptake of [(11)C]befloxatone in Bcrp-deficient rats influenced by the inhibition of P-gp. In conclusion, the Bcrp-deficient rat strain, in which we detected no compensatory mechanism or modification of P-gp expression as compared to WT rats, is a suitable model to study Bcrp function separately from that of P-gp at the BBB. However, although selectively transported by BCRP in vitro, our results suggest that [(11)C]befloxatone PET imaging might not be biased by impaired function of this transporter in vivo.
authors: INSERM U705, CNRS UMR8206, Faculté de Pharmacie, Université Paris Descartes, Sorbonne Paris Cité, Université Paris Diderot, Paris F-75006, France.
authors: Benoit
authors: B
authors: Hosten
authors: Raphaël
authors: R
authors: Boisgard
authors: Aude
authors: A
authors: Jacob
authors: Sébastien
authors: S
authors: Goutal
authors: Bruno
authors: B
authors: Saubaméa
authors: Frédéric
authors: F
authors: Dollé
authors: Jean-Michel
authors: JM
authors: Scherrmann
authors: Salvatore
authors: S
authors: Cisternino
authors: Nicolas
authors: N
authors: Tournier
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D008297:Male; D010080:Oxazoles / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D051381:Rats; D055647:Rats, Transgenic / Q000378:metabolism*; D017208:Rats, Wistar
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C489249:Abcg2 protein, rat; D010080:Oxazoles; C090014:befloxatone
keywords: ABC-transporters; Befloxatone; Blood–brain barrier; Compensation; Monoamine oxidase A (MAO-A); Positron emission tomography