title: The brain entry of risperidone and 9-hydroxyrisperidone is greatly limited by P-glycoprotein.
abstract: P-glycoprotein (P-gp) in the brain capillary endothelial cell limits the entry of many drugs into the brain. Our previous in-vitro study using ATPase as a marker of P-gp activity suggested that risperidone might be effectively transported by P-gp. In the present study, we compared the concentrations of risperidone and its major pharmacologically active metabolite 9-hydroxyrisperidone (9-OH-risperidone), in plasma, brain and various other tissues between abcb1ab-/- knockout mice which are functionally devoid of P-gp in their blood-brain barrier vs. FVB wild-type mice. One hour after intraperitoneal injection of 4 microg/g risperidone, the brain concentrations and ratios of brain:plasma concentrations of risperidone (13.1-fold and 12-fold respectively, p<0.05) and 9-OH-risperidone (29.4-fold and 29-fold respectively, p<0.01) were significantly higher in the abcb1ab-/- mice than those in the FVB mice. These results indicate that P-gp in the blood-brain barrier significantly influences the brain concentrations of risperidone and 9-OH-risperidone by limiting their CNS access.
authors.affiliation: Laboratory of Drug Disposition and Pharmacogenetics, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Jun-Sheng
authors.initials: JS
authors.lastname: Wang
authors.forename: Ying
authors.initials: Y
authors.lastname: Ruan
authors.forename: Robin M
authors.initials: RM
authors.lastname: Taylor
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Donovan
authors.forename: John S
authors.initials: JS
authors.lastname: Markowitz
authors.forename: C Lindsay
authors.initials: CL
authors.lastname: DeVane
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D007274:Injections, Intraperitoneal; D007555:Isoxazoles / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D000068882:Paliperidone Palmitate; D011743:Pyrimidines / Q000493:pharmacokinetics*; D018967:Risperidone / Q000493:pharmacokinetics*; D012702:Serotonin Antagonists / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007555:Isoxazoles; D011743:Pyrimidines; D012702:Serotonin Antagonists; D018967:Risperidone; D000068882:Paliperidone Palmitate