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

Drug Metab Lett. 2012 Oct 5;

Authors: Kallem R, Kulkarni CP, Patel D, Thakur M, Sinz M, Singh SP, Mahammad SS, Mandlekar S


In the present study we have developed a simple, time and cost effective in vivo rodent protocol to screen a test compound susceptibility 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 compund provides a cost efective alternative to expensive P-gp knockout mice models during early drug discovery evaluations.

PMID: 23061481 [PubMed - as supplied by publisher]