title: The influence of the P-glycoprotein inhibitor zosuquidar trihydrochloride (LY335979) on the brain penetration of paclitaxel in mice.
abstract: 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.
authors: Department of Clinical Chemistry, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Huis, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors: E Marleen
authors: EM
authors: Kemper
authors: Cindy
authors: C
authors: Cleypool
authors: Willem
authors: W
authors: Boogerd
authors: Jos H
authors: JH
authors: Beijnen
authors: Olaf
authors: O
authors: van Tellingen
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D000284:Administration, Oral; D000465:Algorithms; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003986:Dibenzocycloheptenes / Q000494:pharmacology*; D005260:Female; D007275:Injections, Intravenous; D051379:Mice; D018345:Mice, Knockout; D017239:Paclitaxel / Q000493:pharmacokinetics*; D011804:Quinolines / Q000494:pharmacology*; D013056:Spectrophotometry, Ultraviolet; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D003986:Dibenzocycloheptenes; D011804:Quinolines; C095179:zosuquidar trihydrochloride; D017239:Paclitaxel