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Drug Metabolism Letters


ISSN (Print): 1872-3128
ISSN (Online): 1874-0758

A Simplified Protocol Employing Elacridar in Rodents: A Screening Model in Drug Discovery to Assess P-gp Mediated Efflux at the Blood Brain Barrier

Author(s): Rajareddy Kallem, Chetan P. Kulkarni, Dakshay Patel, Megha Thakur, Michael Sinz, Sheelendra P. Singh, S. Shahe Mahammad and Sandhya Mandlekar

Volume 6 , Issue 2 , 2012

Page: [134 - 144] Pages: 11

DOI: 10.2174/1872312811206020134

Price: $65


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.

Keywords: Blood brain barrier, Brain to plasma ratio, Digoxin, Elacridar, P-glycoprotein, Pharmacokinetics, Quinidine

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