Pharmacokinetic consequences of active drug efflux at the blood-brain barrier

Pharm Res. 2006 Apr;23(4):705-17. doi: 10.1007/s11095-006-9780-0. Epub 2006 Apr 7.


Purpose: The objective of this simulation study was to investigate how the nature, location, and capacity of the efflux processes in relation to the permeability properties influence brain concentrations.

Methods: Reduced brain concentrations can be due to either influx hindrance, a gatekeeper function in the luminal membrane, which has been suggested for ABCB1 (P-glycoprotein), or efflux enhancement by transporters that pick up molecules on one side of the luminal or abluminal membrane and release them on the other side. Pharmacokinetic models including passive transport, influx hindrance, and efflux enhancement were built using the computer program MATLAB. The simulations were based on experimentally obtained parameters for morphine, morphine-3-glucuronide, morphine-6-glucuronide, and gabapentin.

Results: The influx hindrance process is the more effective for keeping brain concentrations low. Efflux enhancement decreases the half-life of the drug in the brain, whereas with influx hindrance the half-life is similar to that seen with passive transport. The relationship between the influx and efflux of the drug across the blood-brain barrier determines the steady-state ratio of brain to plasma concentrations of unbound drug, K(p,uu).

Conclusions: Both poorly and highly permeable drugs can reach the same steady-state ratio, although the time to reach steady state will differ. The volume of distribution of unbound drug in the brain does not influence K(p,uu), but does influence the total brain-to-blood ratio K(p) and the time to reach steady state in the brain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Algorithms
  • Blood-Brain Barrier / metabolism*
  • Carrier Proteins / metabolism
  • Chemical Phenomena
  • Chemistry, Physical
  • Computer Simulation
  • Diffusion
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / metabolism
  • Half-Life
  • Models, Statistical
  • Pharmaceutical Preparations / metabolism*
  • Pharmacokinetics*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Carrier Proteins
  • Pharmaceutical Preparations