The influence of the P-glycoprotein inhibitor zosuquidar trihydrochloride (LY335979) on the brain penetration of paclitaxel in mice

Cancer Chemother Pharmacol. 2004 Feb;53(2):173-8. doi: 10.1007/s00280-003-0720-y. Epub 2003 Nov 7.


We determined the effect of zosuquidar.3HCl, an inhibitor of P-gp, on the penetration of the anticancer drug paclitaxel into the brain. Zosuquidar.3HCl was administered orally at 25 and 80 mg/kg 1 h before i.v. paclitaxel and i.v. at 20 mg/kg 10 min and 1 h before paclitaxel. The concentrations of paclitaxel in plasma and tissues and of zosuquidar.3HCl in plasma were quantified by high-performance liquid chromatography. The results revealed 3.5-fold and 5-fold higher paclitaxel levels in the brain of wild-type mice treated orally with 25 and 80 mg/kg zosuquidar.3HCl, respectively. However, complete inhibition as in P-gp knockout mice (11-fold increase) was not achieved. Zosuquidar.3HCl also increased the paclitaxel concentrations in plasma and tissues to levels similar to those observed in P-gp knockout mice, suggesting selective P-gp inhibition of zosuquidar.3HCl. When zosuquidar.3HCl was administered i.v. 10 min before paclitaxel, the paclitaxel levels in the brain of wild-type mice increased by 5.6-fold, whereas the increase was only 2.1-fold when zosuquidar.3HCl was administered 1 h before paclitaxel. This suggests that the inhibition of P-gp at the blood-brain barrier by zosuquidar.3HCl is rapidly reversible and that the concentrations of zosuquidar.3HCl in the plasma have already declined to levels insufficient to inhibit P-gp at the blood-brain barrier. In conclusion, zosuquidar.3HCl is only moderately active as an inhibitor of P-gp at the blood-brain barrier.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • Administration, Oral
  • Algorithms
  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacokinetics*
  • Area Under Curve
  • Biological Availability
  • Brain / drug effects
  • Brain / metabolism*
  • Dibenzocycloheptenes / pharmacology*
  • Female
  • Injections, Intravenous
  • Mice
  • Mice, Knockout
  • Paclitaxel / pharmacokinetics*
  • Quinolines / pharmacology*
  • Spectrophotometry, Ultraviolet
  • Tissue Distribution


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents, Phytogenic
  • Dibenzocycloheptenes
  • Quinolines
  • zosuquidar trihydrochloride
  • Paclitaxel