Development of a P-glycoprotein knockout model in rodents to define species differences in its functional effect at the blood-brain barrier

被引:42
作者
Cutler, Leanne [1 ]
Howes, Colin [1 ]
Deeks, Nigel J. [1 ]
Buck, Tania L. [1 ]
Jeffrey, Phil [1 ]
机构
[1] GlaxoSmithKline R&D, Neurol & Gastrointestinal Ctr Excellence Drug Dis, Dept Drug Metab & Pharmacokinet, Harlow CM19 5AW, Essex, England
关键词
P-glycoprotein; CNS; blood-brain barrier; pharmacokinetics; inhibition; GF120918; rat; mouse; guinea pig;
D O I
10.1002/jps.20658
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The objective of this study was to establish the optimal blood concentrations of the potent P-glycoprotein (P-gp) inhibitor GF120918 (Elacridar) required to achieve maximal knockout of this efflux transporter in the blood-brain barrier (BBB) of mice, rats, and guinea pigs. Genetic mdr1a/b(-/-) knockout mice and "chemical" P-gp knockout mice, rats, and guinea pigs, generated by 24 h continuous infusion of GF120918, were used to investigate the effects of P-gp modulation on the brain penetration of SB-487946. Genetic mdr1a/b(-/-) knockout mice demonstrated a > 70-fold increase in brain:blood ratio of SB-487946 compared to mdr1a/b(+/+) wild-type mice. There was a similar increase in SB-487946 brain:blood ratio in GF120918-treated mice (ca. > 67-fold) and rats (ca. 95-fold) but a significantly smaller increase (ca. 10-fold) in guinea pigs treated with GF120918. An appreciable difference was found in the BBB functional effect of P-gp efflux in rodents. GF120918 blood EC90 in mice and rats were similar however, the EC90 in guinea pigs was ca. 10-fold higher, suggesting a species difference in the activity of P-gp at the BBB in some rodents. This study establishes the optimal blood concentrations of GF120918 in relation to SB-487946, to achieve chemically induced P-gp knockout in rodents. (c) 2006 Wiley-Liss, Inc.
引用
收藏
页码:1944 / 1953
页数:10
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