Differential enhancement of antidepressant penetration into the brain in mice with abcb1ab (mdr1ab) P-glycoprotein gene disruption

Biol Psychiatry. 2003 Oct 15;54(8):840-6. doi: 10.1016/s0006-3223(03)00074-x.

Abstract

Background: Mice with a genetic disruption (knockout) of the multiple drug resistance (abcb1ab) gene were used to examine the effect of the absence of the drug-transporting P-glycoprotein (P-gp) at the blood-brain barrier on the uptake of the antidepressants venlafaxine, paroxetine, mirtazapine, and doxepin and its metabolites into the brain.

Methods: One hour after subcutaneous injection of venlafaxine, paroxetine, mirtazapine, or doxepin, knockout and wildtype mice were sacrificed, and the drug concentrations in brain, spleen, kidney, liver, and plasma were measured.

Results: The cerebrum concentrations of doxepin, venlafaxine, and paroxetine were higher in knockout mice, demonstrating that these substances are substrates of P-gp and that abcb1ab activity at the level of the blood-brain barrier reduces the penetration of these substances into the brain. In contrast, brain distribution of mirtazapine was indistinguishable between the groups.

Conclusions: The differences reported here in brain penetration of antidepressant drugs that depend on the presence of the abcb1ab gene may offer an explanation for poor or nonresponse to antidepressant treatment. Furthermore, they may be able to explain in part the discrepancies between plasma levels of an antidepressant and its clinical effects and side effects.

Publication types

  • Comparative Study

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • ATP-Binding Cassette Transporters / genetics*
  • Animals
  • Antidepressive Agents / administration & dosage
  • Antidepressive Agents / blood
  • Antidepressive Agents / pharmacokinetics*
  • Blood-Brain Barrier / drug effects
  • Brain / metabolism*
  • Chromatography, High Pressure Liquid
  • Cyclohexanols / administration & dosage
  • Cyclohexanols / blood
  • Cyclohexanols / pharmacokinetics
  • Doxepin / administration & dosage
  • Doxepin / blood
  • Doxepin / pharmacokinetics
  • Drug Resistance, Multiple / genetics*
  • Gene Expression / genetics
  • Injections, Subcutaneous
  • Kidney / metabolism
  • Liver / metabolism
  • Male
  • Mianserin / administration & dosage
  • Mianserin / analogs & derivatives*
  • Mianserin / blood
  • Mianserin / pharmacokinetics
  • Mice
  • Mice, Knockout
  • Mirtazapine
  • Paroxetine / administration & dosage
  • Paroxetine / blood
  • Paroxetine / pharmacology
  • Point Mutation / genetics*
  • Spleen / metabolism
  • Venlafaxine Hydrochloride

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP-Binding Cassette Transporters
  • Antidepressive Agents
  • Cyclohexanols
  • P-glycoprotein 2
  • Doxepin
  • Mianserin
  • Paroxetine
  • Venlafaxine Hydrochloride
  • multidrug resistance protein 3
  • Mirtazapine