Abstract
Elacridar (GF120918) is a highly potent inhibitor of both P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2), the main efflux transporters expressed at the blood-brain barrier (BBB). Elacridar shows very low aqueous solubility, which complicates its formulation for i.v. administration. An intravenous infusion protocol would be preferred to achieve high and controlled plasma concentrations of elacridar in large animals, including nonhuman primates. Formulation of elacridar for i.v. infusion was achieved using a co-solvent strategy, resulting in an aqueous dispersion with a final concentration of 5 g L−1 elacridar with tetrahydrofuran (5% w/v) in aqueous D-glucose solution (2.5%, w/v). Particle size (mean = 2.8 ± 0.9 μm) remained stable for 150 min. The preparation was i.v. administered as a continuous infusion (12 mg kg−1 h−1 for 90 min) to three baboons. Arterial and venous plasma pharmacokinetics (PK) of elacridar were monitored using a newly developed and validated HPLC-UV method. Elacridar concentration increased rapidly to reach a plateau at 9.5 μg mL−1 within 20 min after the start of infusion. Elacridar PK in venous plasma did not differ from arterial plasma facing the BBB, indicating the absence of an arteriovenous concentration gradient. Intravenous infusion of elacridar allows for controlled exposure of the BBB and offers a useful tool to assess the impact of ABCB1/ABCG2 on drug disposition to the brain in nonhuman primates, a relevant animal model for the study of transporter function at the BBB.
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Abbreviations
- ABC:
-
ATP-binding cassette
- BBB:
-
Blood-brain barrier
- CSs:
-
Calibration standards
- CNS:
-
Central nervous system
- IS:
-
Internal standard
- i.v.:
-
Intravenous
- C max :
-
Maximum plasma concentration
- PK:
-
Pharmacokinetics
- PDI:
-
Polydispersity index
- QCs:
-
Quality controls
- THF:
-
Tetrahydrofuran
- TKIs:
-
Tyrosine kinase inhibitors
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Acknowledgements
We thank Jérôme Cayla for helpful technical assistance during nonhuman primate experiments. Animal experiments were performed on a platform of France Life Imaging network partly funded by the grant “ANR-11-INBS-0006”. The Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS, CNRS UMR 8258, Inserm U1022. CNRS UMR 8258, Inserm U1022) is acknowledged for kind help regarding the characterization of the preparation.
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Characterization of the preparation was supervised by Karine Andrieux. She participated in the preparation, revision, and approval of the final manuscript. All authors have approved the final manuscript.
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All institutional and national guidelines for the care and use of laboratory animals were followed.
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The authors declare that they have no conflict of interest.
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Goutal, S., Langer, O., Auvity, S. et al. Intravenous infusion for the controlled exposure to the dual ABCB1 and ABCG2 inhibitor elacridar in nonhuman primates. Drug Deliv. and Transl. Res. 8, 536–542 (2018). https://doi.org/10.1007/s13346-017-0472-6
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DOI: https://doi.org/10.1007/s13346-017-0472-6