A simplified protocol employing elacridar in rodents: a screening model in drug discovery to assess P-gp mediated efflux at the blood brain barrier

• Published in: Drug metabolism letters Vol. 6; no. 2; p. 134
• Main Authors: Kallem, Rajareddy, Kulkarni, Chetan P, Patel, Dakshay, Thakur, Megha, Sinz, Michael, Singh, Sheelendra P, Mahammad, S Shahe, Mandlekar, Sandhya
• Format: Journal Article
• Language: English
• Published: United Arab Emirates 01-06-2012
• Subjects: Acridines - administration & dosage; Acridines - pharmacology; Animals; Area Under Curve; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological Transport; Blood-Brain Barrier - metabolism; Brain - metabolism; Chromatography, Liquid; Cost-Benefit Analysis; Digoxin - pharmacokinetics; Drug Design; Drug Interactions; Half-Life; Injections, Intravenous; Male; Mice; Propanolamines - pharmacokinetics; Quinidine - pharmacokinetics; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry; Tetrahydroisoquinolines - administration & dosage; Tetrahydroisoquinolines - pharmacology; Time Factors; Tissue Distribution
• ISSN: 1874-0758

In the present study we have developed a simple, time, and cost effective in vivo rodent protocol to screen the susceptibility of a test compound for P-glycoprotein (P-gp) mediated efflux at the blood brain barrier (BBB) during early drug discovery. We used known P-gp substrates as test compounds (quinidine, digoxin, and talinolol) and elacridar (GF120918) as a chemical inhibitor to establish the model. The studies were carried out in both mice and rats. Elacridar was dosed intravenously at 5 mg/kg, 0.5 h prior to probe substrate administration. Plasma and brain samples were collected and analyzed using UPLC-MS/MS. In the presence of elacridar, the ratio of brain to plasma area under the curve (B/P) in mouse increased 2, 4, and 38-fold, respectively, for talinolol, digoxin, and quinidine; whereas in rat, a 70-fold increase was observed for quinidine. Atenolol, a non P-gp substrate, exhibited poor brain penetration in the presence or absence of elacridar in both species (B/P ratio ~ 0.1). Elacridar had no significant effect on the systemic clearance of digoxin or quinidine; however, a trend towards increasing volume of distribution and half life was observed. Our results support the utility of elacridar in evaluation of the influence of P-gp mediated efflux on drug distribution to the brain. Our protocol employing a single intravenous dose of elacridar and test compound provides a cost effective alternative to expensive P-gp knockout mice models during early drug discovery.