title: An in vivo microdialysis study of FLZ penetration through the blood-brain barrier in normal and 6-hydroxydopamine induced Parkinson's disease model rats.
abstract: FLZ (N-[2-(4-hydroxy-phenyl)-ethyl]-2-(2,5-dimethoxy-phenyl)-3-(3-methoxy-4-hydroxy-phenyl)-acrylamide) is a novel synthetic squamosamide derivative and a potential anti-Parkinson's disease (PD) agent. The objective of the present study was to investigate the penetration of free FLZ across the BBB and the effects of P-gp inhibition on FLZ transport in normal and 6-hydroxydopamine (6-OHDA) induced PD model rats. In vivo microdialysis was used to collect FLZ containing brain and blood dialysates following intravenous (i.v.) drug administration either with or without pretreatment with the specific P-gp inhibitor, zosuquidar trihydrochloride (zosuquidar·3HCl). A sensitive, rapid, and reliable ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) technique was developed and validated to quantitate free FLZ levels in the dialysates. No significant differences were observed in the brain/blood FLZ area under the concentration-time curve (AUC) ratio between normal and PD model rats. However, pretreatment with zosuquidar·3HCl markedly increased the AUC ratio in both rat models. In addition, FLZ penetration was similar in zosuquidar·3HCl-pretreated normal and PD rats. These results suggest that P-gp inhibition increases BBB permeability to FLZ, thereby supporting the hypothesis that P-gp normally restricts FLZ transfer to the brain. These findings could provide reference data for future clinical trials and may aid investigation of the BBB permeability of other CNS-active substances.
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Hou
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Yingfei
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Jinlan
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D044482:Benzeneacetamides / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier; D003986:Dibenzocycloheptenes / Q000008:administration & dosage; D006801:Humans; D017551:Microdialysis; D016627:Oxidopamine / Q000633:toxicity; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D010636:Phenols / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D011804:Quinolines / Q000008:administration & dosage; D051381:Rats; D053719:Tandem Mass Spectrometry
chemical_list: D044482:Benzeneacetamides; D003986:Dibenzocycloheptenes; D010636:Phenols; D011804:Quinolines; C084439:squamosamide; C095179:zosuquidar trihydrochloride; D016627:Oxidopamine