Drug Metabolism and Disposition Brain distribution and bioavailability of elacridar after different routes of administration in the mouse

This article has not been copyedited and formatted. The final version may differ from this version. Abstract: The objective of this study was to determine the bioavailability and disposition of elacridar (GF120918) in plasma and brain after various routes of administration in the mouse. Elacridar is a potent inhibitor of P-gp and BCRP and has been used to examine the influence of these efflux transporters on drug distribution to brain. FVB 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 hours after intraperitoneal and intravenous administration, and nearly 20 hours 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. This article has not been copyedited and formatted. The final version may differ from this version.