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

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-tran sporting P-glycoprotein at the blood-brain barrier on the uptake of amitrip tyline (AMI) and fluoxetine (FLU) and their metabolites into the brain. One hour after intraperitoneal injection of AMI or FLU, knockout (-/-) and wil d-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, demonstrat ing that AMI and its metabolites are substrates of the P-glycoprotein and t hat mdr1a activity at the level of the blood-brain barrier reduces the pene tration of these substances into the brain. In contrast, tissue distributio ns of FLU and its metabolites among the various tissues tested were indisti nguishable between groups. The herein reported differences in brain penetra tion of antidepressant drugs depending on the presence of the mdr1a gene ma y offer an explanation for differences in the treatment response at a given plasma concentration. Moreover, individual differences in mdr1 gene activi ty may account for variable response patterns at different episodes and dev elopment of therapy resistance.