Penetration of amitriptyline, but not of fluoxetine, into brain is enhanced in mice with blood-brain barrier deficiency due to Mdr1a P-glycoprotein gene disruption

被引:185
作者
Uhr, M [1 ]
Steckler, T [1 ]
Yassouridis, A [1 ]
Holsboer, F [1 ]
机构
[1] Max Planck Inst Psychiat, D-80804 Munich, Germany
关键词
amitriptyline; fluoxetine; multiple drug resistance gene; P-glycoprotein; mousemutants; therapy resistance;
D O I
10.1016/S0893-133X(99)00095-0
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Mice with a genetic disruption (knockout) of the multiple drug resistance (Mdr1a) gene were used to examine the effect of the absence of the drug-transporting P-glycoprotein at the blood-brain barrier on the uptake of amitriptyline (AMI) and fluoxetine (FLU) and their metabolites into the brain. One hour after intraperitoneal injection of AMI or FLU, knockout (-/-) and wild-type (+/+) mice were sacrificed and drug concentrations of brain, kidney, liver, testis, and plasma were measured. The plasma concentrations of the AMI metabolites and the brain:spleen ratios of AMI, nortriptyline (NOR), 10-OH-AMI and 10-OH-NOR were significantly higher in the -/- mice, demonstrating that AMI and its metabolites are substrates of the P-glycoprotein and that mdr1a activity at the level of the blood-brain barrier reduces the penetration of these substances into the brain. In contrast, tissue distributions of FLU and its metabolites among the various tissues tested were indistinguishable between groups. The herein reported differences in brain penetration of antidepressant drugs depending on the presence of the mdr1a gene may offer an explanation for differences in the treatment response at a given plasma concentration. Moreover, individual differences in mdr1 gene activity may account for variable response patterns at different episodes and development of therapy resistance.
引用
收藏
页码:380 / 387
页数:8
相关论文
共 25 条
[21]   IMMUNOHISTOCHEMICAL LOCALIZATION IN NORMAL-TISSUES OF DIFFERENT EPITOPES IN THE MULTIDRUG TRANSPORT PROTEIN P170 - EVIDENCE FOR LOCALIZATION IN BRAIN CAPILLARIES AND CROSSREACTIVITY OF ONE ANTIBODY WITH A MUSCLE PROTEIN [J].
THIEBAUT, F ;
TSURUO, T ;
HAMADA, H ;
GOTTESMAN, MM ;
PASTAN, I ;
WILLINGHAM, MC .
JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY, 1989, 37 (02) :159-164
[22]   CELLULAR-LOCALIZATION OF THE MULTIDRUG-RESISTANCE GENE-PRODUCT P-GLYCOPROTEIN IN NORMAL HUMAN-TISSUES [J].
THIEBAUT, F ;
TSURUO, T ;
HAMADA, H ;
GOTTESMAN, MM ;
PASTAN, I ;
WILLINGHAM, MC .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1987, 84 (21) :7735-7738
[23]   Blood-brain barrier function of P-glycoprotein [J].
Tsuji, A ;
Tamai, I .
ADVANCED DRUG DELIVERY REVIEWS, 1997, 25 (2-3) :287-298
[24]   P-GLYCOPROTEIN AS THE DRUG EFFLUX PUMP IN PRIMARY CULTURED BOVINE BRAIN CAPILLARY ENDOTHELIAL-CELLS [J].
TSUJI, A ;
TERASAKI, T ;
TAKABATAKE, Y ;
TENDA, Y ;
TAMAI, I ;
YAMASHIMA, T ;
MORITANI, S ;
TSURUO, T ;
YAMASHITA, J .
LIFE SCIENCES, 1992, 51 (18) :1427-1437
[25]  
van de Vrie W, 1998, CRIT REV CL LAB SCI, V35, P1