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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: 7.83). 05/2000; 22(4):380-7. DOI: 10.1016/S0893-133X(99)00095-0
Source: PubMed

ABSTRACT 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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    • "Taken together, these data suggest that the brain pharmacokinetics of certain compounds may differ between single knockout abcb1a (-/-) mice and double knockout abcb1ab (-/-) mice. Furthermore, the data from Uhr and co-workers were from a single time point (1 h) following fluoxetine administration (Uhr et al., 2000); Doran and colleagues, on the other hand, took samples at various time points (Doran et al., 2005). Therefore, the impact of P-gp on fluoxetine distribution may be time- dependent. "
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    • "Because of its location at the blood–brain barrier, Pgp may regulate the concentration of ADs in the brain. For paroxetine, venlafaxine, and fluoxetine the data indicate that they might be Pgp substrates; for citalopram the data are conflicting (Rochat et al., 1999; Uhr et al., 2000). Several variants of ABCB1 are known (Kioka et al., 1989; Mickley et al., 1998; Hoffmeyer et al., 2000; Ito et al., 2001), among these three – C3435T (rs1045642), C1236 (rs1128503), and G2677T (rs2032582) – have been associated with altered Pgp activity. "
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    • "Two distinct G protein-coupled receptors have been characterized that mediate the biological actions of CRH: CRHR1 and CRHR2. These two receptors display a markedly different tissue distribution and pharmacological specificity (Lopez et al., 1998; Uhr et al., 2000). Numerous investigations in animals have described anxiogenic like effects after central CRH elevation (Dunn and Berridge, 1990; Sanchez et al., 1994). "
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