Effect of mdr1a P-glycoprotein gene disruption, gender, and substrate concentration on brain uptake of selected compounds

被引:60
作者
Dagenais, C
Zong, J
Ducharme, J
Pollack, GM [1 ]
机构
[1] Univ N Carolina, Sch Pharm, Div Drug Delivery & Disposit, Chapel Hill, NC 27599 USA
[2] AstraZeneca R&D Montreal, St Laurent, PQ H4S 1Z9, Canada
[3] Univ Montreal, Fac Pharm, Montreal, PQ H3C 3J7, Canada
[4] Univ Montreal, Dept Anesthesiol, Montreal, PQ H3C 3J7, Canada
关键词
P-glycoprotein; mdr1a(-/-) mice; morphine; verapamil; quinidine; blood-brain barrier; plasma protein binding;
D O I
10.1023/A:1010984110732
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Purpose. This study assessed the influence of nldr1a P-glycoprotein (P-gp) gene disruption, gender and concentration on initial brain uptake clearance (Cl-up) of morphine, quinidine and verapamil. Methods. Cl-up of radiolabeled substrates was determined in P-gp-competent and deficient [mdrla(-/-)] mice by in situ brain perfusion. Brain:plasma distribution of substrates after i.v. administration was determined in both strains. Results, Genetic disruption of mdrla P-gp resulted in 1.3-, 6.6- and 14-fold increases in Cl-up for morphine, verapamil and quinidine, respectively. With the exception of small differences for verapamil, gender did not affect Cl-up. Saturable transport of verapamil and quinidine was observed only in P-gp-competent mice, with apparent IC50 values for efflux of 8.6 +/- 2.3 muM and 36 +/- 2 muM, respectively. Verapamil Cl-up was similar to 50% higher in mdrla(+/-) vs. mdrla(+/+) mice: no such difference was observed for quinidine. In P-gp-competent mice, uptake of verapamil and quinidine was unaffected by organic vehicles. Plasma decreased VER Cl-up to a greater extent in the presence of P-gp. The influence of P-gp in situ was lower than, but correlated with, the effect in vivo. Conclusions. P-gp decreases Cl-up of morphine, verapamil and quinidine in situ with little or no influence of gender, but this effect cannot fully account for the effects of P-gp in vivo. P-gp is the only saturable transport mechanism for verapamil and quinidine at the murine blood-brain barrier. The influence of protein binding on Cl-up may be enhanced by P-gp-mediated efflux.
引用
收藏
页码:957 / 963
页数:7
相关论文
共 32 条
[1]   MULTIDRUG RESISTANCE GENE-EXPRESSION IS CONTROLLED BY STEROID-HORMONES IN THE SECRETORY EPITHELIUM OF THE UTERUS [J].
ARCECI, RJ ;
BAAS, F ;
RAPONI, R ;
HORWITZ, SB ;
HOUSMAN, D ;
CROOP, JM .
MOLECULAR REPRODUCTION AND DEVELOPMENT, 1990, 25 (02) :101-109
[2]  
Bain LJ, 1996, TOXICOL APPL PHARM, V141, P288, DOI 10.1016/S0041-008X(96)80035-4
[3]  
Bickel U, 1996, J PHARMACOL EXP THER, V278, P107
[4]  
CHIKHALE EG, 1995, J PHARMACOL EXP THER, V273, P298
[5]   Screening of multidrug-resistance sensitive drugs by in situ brain perfusion in P-glycoprotein-deficient mice [J].
Cisternino, S ;
Rousselle, C ;
Dagenais, C ;
Scherrmann, JM .
PHARMACEUTICAL RESEARCH, 2001, 18 (02) :183-190
[6]   Development of an in situ mouse brain perfusion model and its application to mdr1a P-glycoprotein-deficient mice [J].
Dagenais, C ;
Rousselle, C ;
Pollack, GM ;
Scherrmann, JM .
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 2000, 20 (02) :381-386
[7]  
Drion N, 1996, J NEUROCHEM, V67, P1688
[8]   CLINICAL-STUDIES WITH MODULATORS OF MULTIDRUG-RESISTANCE [J].
FISHER, GA ;
SIKIC, BI .
HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA, 1995, 9 (02) :363-382
[9]  
FREMSTAD D, 1977, ACTA PHARMACOL TOX, V41, P148
[10]   GENDER DIFFERENCES IN REGIONAL CEREBRAL BLOOD-FLOW [J].
GUR, RE ;
GUR, RC .
SCHIZOPHRENIA BULLETIN, 1990, 16 (02) :247-254