Abstract
The objective of this study was to determine the bioavailability and disposition of elacridar (GF120918; N-(4-(2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl)phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide) in plasma and brain after various routes of administration in the mouse. Elacridar is a potent inhibitor of P-glycoprotein and breast cancer resistance protein and has been used to examine the influence of these efflux transporters on drug distribution to brain. Friend leukemia virus strain B mice were administered 100 mg/kg elacridar either orally or intraperitoneally. The absolute bioavailability of elacridar after oral or intraperitoneal dosing was determined with respect to an intravenous dose of 2.5 mg/kg. At these doses, the absolute bioavailability was 0.22 for oral administration and 0.01 for intraperitoneal administration. The terminal half-life of elacridar was approximately 4 h after intraperitoneal and intravenous administration and nearly 20 h after oral dosing. The brain-to-plasma partition coefficient (Kp,brain) of elacridar increased as plasma exposure increased, suggesting saturation of the efflux transporters at the blood-brain barrier. The Kp,brain after intravenous, intraperitoneal, and oral dosing was 0.82, 0.43, and 4.31, respectively. The low aqueous solubility and high lipophilicity of elacridar result in poor oral absorption, most likely dissolution-rate-limited. These results illustrate the importance of the route of administration and the resultant plasma exposure in achieving effective plasma and brain concentrations of elacridar and can be used as a guide for future studies involving elacridar administration and in developing formulation strategies to overcome the poor absorption.
Footnotes
This work was supported by the National Institutes of Health National Cancer Institute [Grant CA138437] (to W.F.E.); and a Faculty Development Grant at the University of Minnesota (to W.F.E.). S.A. was supported by a doctoral dissertation fellowship from the University of Minnesota. R.S. was supported by the Ronald J. Sawchuk Fellowship and Rowell Fellowship.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
ABBREVIATIONS:
- GF120918
- N-(4-(2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl)phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide
- P-gp
- P-glycoprotein
- BCRP
- breast cancer resistance protein
- BBB
- blood-brain barrier
- TKI
- tyrosine kinase inhibitor
- FVB
- Friend leukemia virus strain B
- AUC
- area under the concentration-time curve
- AUC0-inf
- AUC from time zero to infinity.
- Received March 28, 2012.
- Accepted May 18, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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