Antidepressive drugs as substrates of P-glycoprotein at the blood brain barrier

The ABCB1 transport protein, the gene product of the so-called multi-drug resistance gene, is a transmembrane protein, which exports substrates in an energy-dependent manner against a concentration gradient out of the cell. P-glycoprotein is expressed in endothelial cells that constitute the blood-brain barrier on the side facing the blood vessel lumina. It prevents the penetration of its substrates into the brain.

Using abcb1ab (-/-) double knock-out mice without functioning P-glycoprotein and control mice, we showed that important and clinically popular drugs are substrates of P-glycoprotein. These substrates include the antidepressants amitriptyline and its metabolites, citalopram, venlafaxine, paroxetine and others. P-glycoprotein affects their ability to penetrate into the brain. Other drugs, such as fluoxetine or mirtazapine are not substrates of P-glycoprotein, which therefore does not impair their ability to cross the blood-brain barrier. These studies led to the hypothesis that individual changes in the transport protein can result in differing cerebral concentrations in different patients. Resulting low cerebral drug concentrations could explain the development of therapy resistance in certain patients.

(Antidepressiva als Substrate von P-Glycoprotein an der Blut-Hirn-Schranke)