Donepezil, a cholinesterase inhibitor used in Alzheimer's disease therapy, is actively exported out of the brain by abcb1ab p-glycoproteins in mice

J Psychiatr Res. 2020 May:124:29-33. doi: 10.1016/j.jpsychires.2020.01.012. Epub 2020 Jan 27.

Abstract

Polymorphisms in the drug transporter gene ABCB1 predict the treatment response of selected antidepressants and limit anticonvulsive medication's effectiveness. The ABCB1 locus encodes the energy-dependent transporter P-glycoprotein (P-gp) of the blood brain barrier (BBB), which serves as an efflux pump of its substrates in the expressing tissues of vertebrates. One experimental setup to determine a posteriori the P-gp substrate status is the use of the double abcb1ab knock-out (KO) mice model. Since so far, P-gp substrate status of donepezil, a cholinesterase inhibitor wildly used in Alzheimer's disease therapy was inconclusive, we performed subcutanous (s.c.), continuous injections over 11 days in double abcb1ab KO and P-gp competent wildtype (WT) mice. Both in brain and in testis concentrations of donepezil were significantly higher in P-gp deficient mice compared to WT controls (2.39 and 2.24 times respectively). In conclusion, in mice donepezil's brain bioavailability depends on P-gp.

Keywords: ABCB1; Blood–brain barrier; Donepezil; P-glycoprotein (P-gp); abcb1ab knock-out mice.

Publication types

  • Research Support, Non-U.S. Gov't

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
  • Alzheimer Disease* / drug therapy
  • Alzheimer Disease* / genetics
  • Animals
  • Blood-Brain Barrier / metabolism
  • Brain / metabolism
  • Cholinesterase Inhibitors* / pharmacology
  • Donepezil
  • Male
  • Mice
  • Mice, Knockout

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Cholinesterase Inhibitors
  • Donepezil