Uhr M, Steckler T, Yassouridis A, Holsboer F. 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. Neuropsychopharmacol 22: 380-387

Max Planck Institute of Psychiatry, Munich, Germany.
Neuropsychopharmacology (Impact Factor: 7.05). 05/2000; 22(4):380-7. DOI: 10.1016/S0893-133X(99)00095-0
Source: PubMed


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.

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Available from: Alexander Yassouridis, Jul 09, 2014
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    • "More than ten years ago, Uhr et al. have started to investigate the influence of the P-glycoprotein (P-gp), a drug efflux pump at the blood-brain barrier which is encoded by the ABCB1 gene, on the penetration of different classes of antidepressant into the brain in a transgenic mouse model. Using those animals deficient of P-gp, they could show that many antidepressants are substrates of the P-gp, among them, for example, widely prescribed compounds such as paroxetine and venlafaxine as well as tricyclic compounds like amitriptyline [41, 42]. They later translated their preclinical findings into the clinic and could finally show that polymorphisms in the ABCB1 gene predict the response to antidepressant treatment in those depressed patients receiving drugs that had previously been identified as substrates of ABCB1 using double-knockout mice. "
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