The study objective was to develop a formulation of elacridar to overcome its dissolution-rate-limited bioavailability. Elacridar is a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitor that has been used to improve the brain distribution of drugs that are substrates of P-gp and BCRP. The chronic use of elacridar is restricted because of the poor solubility leading to poor oral bioavailability. A microemulsion formulation using Cremophor EL, Carbitol, and Captex 355 (6:3:1) was developed. The elacridar microemulsion was effective in the inhibition of P-gp and Bcrp in Madin-Darby canine kidney II-transfected cells. Friend Leukemia Virus Strain B (FVB) mice were used to determine the bioavailability of elacridar after a 10 mg/kg dose of elacridar in the microemulsion, intraperitoneally (i.p.) and orally (p.o.); and the absolute bioavailability was determined to be 1.3 and 0.47, respectively. Coadministration of elacridar microemulsion i.p. with p.o. erlotinib in FVB mice improved the erlotinib brain penetration threefold. The current study shows that a microemulsion formulation of elacridar is effective in improving the bioavailability of elacridar and is an effective inhibitor of P-gp and Bcrp, in vitro and in vivo. It offers an alternative to the suspension and allows a decrease in the dose required to achieve a significant inhibitory effect at the blood-brain barrier.
Bibliographical noteFunding Information:
This work was supported by National Institutes of Health–National Cancer Institute [CA138437] (W.F.E.) and an AHC Faculty Development grant at the University of Minnesota (W.F.E.). Financial support for R.S. was provided by the Ronald J. Sawchuk Fellowship and Rowell Fellowship.
- ABC Transporters
- Preclinical pharmacokinetics
- Target drug delivery