In vivo and in vitro evidence for ATP-dependency of P-glycoprotein-mediated efflux of doxorubicin at the blood-brain barrier

Biochem Pharmacol. 1995 May 17;49(10):1541-4. doi: 10.1016/0006-2952(95)00082-b.


We investigated the role of ATP in the active efflux of doxorubicin (DOX) mediated by P-glycoprotein (P-gp), the multidrug-resistance (MDR) gene product, at the blood-brain barrier. In transient brain ischemic rats prepared with 4-vessel occlusion of vertebral and common carotid arteries for 20 min, a procedure that depleted their brain ATP content to 3% that of normal rats, the estimated permeability coefficient of DOX was increased 17-fold (to 243 +/- 2.5 microL/min/g brain). When the ATP content recovered to a normal level by means of 30-min and 24-hr cerebral recirculation of blood, the permeability coefficient recovered to 14.0 +/- 5.0 and 18.4 +/- 2.3 microL/min/g brain (mean +/- SEM, N = 3-6), respectively, very close to the control permeability (14.3 +/- 1.5 microL/min/g brain). The uptake of DOX by primary cultured brain capillary endothelial cells expressing P-gp at the luminal membrane was increased significantly (up to 2-fold), which correlated well with the decrease of cellular ATP contents caused by treating the cells with metabolic inhibitors. Evidence for the ATP-dependent transport of DOX obtained from the present in vivo and in vitro studies strongly indicates that P-gp in the brain capillaries functions actively as an efflux pump in the physiological state, providing a major mechanism to restrict the transfer of DOX into the brain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / pharmacology
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology*
  • Adenosine Triphosphate / metabolism*
  • Animals
  • Biological Transport
  • Blood-Brain Barrier* / drug effects
  • Cells, Cultured
  • Doxorubicin / metabolism*
  • Endothelium, Vascular / metabolism
  • Ischemic Attack, Transient / metabolism
  • Male
  • Rats


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Doxorubicin
  • Adenosine Triphosphate