title: Development and evaluation of a novel microemulsion formulation of elacridar to improve its bioavailability.
abstract: 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.
authors: Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors: Ramola
authors: R
authors: Sane
authors: Rajendar K
authors: RK
authors: Mittapalli
authors: William F
authors: WF
authors: Elmquist
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000166:Acridines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D000069439:Dasatinib; D004285:Dogs; D016503:Drug Delivery Systems; D004655:Emulsions / Q000737:chemistry; D000069347:Erlotinib Hydrochloride; D006801:Humans; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000493:pharmacokinetics*; D011799:Quinazolines / Q000493:pharmacokinetics*; D012995:Solubility; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013844:Thiazoles / Q000493:pharmacokinetics*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D000166:Acridines; D004655:Emulsions; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D044005:Tetrahydroisoquinolines; D013844:Thiazoles; D000069347:Erlotinib Hydrochloride; C083501:Elacridar; D000069439:Dasatinib