title: Roles of P-glycoprotein and multidrug resistance protein in transporting para-aminosalicylic acid and its N-acetylated metabolite in mice brain.
abstract: OBJECTIVE
  Para-aminosalicylic acid (PAS) is effective in the treatment of manganism-induced neurotoxicity (manganism). In this study we investigated the roles of P-glycoprotein (MDR1a) and multidrug resistance protein (MRP) in transporting PAS and its N-acetylated metabolite AcPAS through blood-brain barrier.
  
  
  METHODS
  MDR1a-null or wild-type mice were intravenously injected with PAS (200 mg/kg). Thirty minutes after the injection, blood samples and brains were collected, and the concentrations of PAS and AcPAS in brain capillaries and parenchyma were measured using HPLC. Both MDCK-MDR1 and MDCK-MRP1 cells that overexpressed P-gp and MRP1, respectively, were used in two-chamber Transwell transport studies in vitro.
  
  
  RESULTS
  After injection of PAS, the brain concentration of PAS was substantially higher in MDR1a-null mice than in wild-type mice, but the brain concentration of AcPAS had no significant difference between MDR1a-null mice and wild-type mice. Concomitant injection of PAS with the MRP-specific inhibitor MK-571 (50 mg/kg) further increased the brain concentration of PAS in MDR1a-null mice, and increased the brain concentration of AcPAS in both MDR1a-null mice and wild-type mice. Two-chamber Transwell studies with MDCK-MDR1 cells demonstrated that PAS was not only a substrate but also a competitive inhibitor of P-gp, while AcPAS was not a substrate of P-gp. Two-chamber Transwell studies with the MDCK-MRP1 cells showed that MRP1 had the ability to transport both PAS and AcPAS across the BBB.
  
  
  CONCLUSIONS
  P-gp plays a major role in the efflux of PAS from brain parenchyma into blood in mice, while MRP1 is involved in both PAS and AcPAS transport in the brain.
authors.affiliation: 1] College of Pharmaceutical Sciences, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Zhejiang University, Hangzhou 310058, China [2] School of Health Sciences, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Hong
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Zhejiang University, Hangzhou 310058, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Xu
authors.affiliation: School of Health Sciences, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Stefanie
authors.initials: S
authors.lastname: O'Neal
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Hui-chang
authors.initials: HC
authors.lastname: Bi
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.affiliation: School of Health Sciences, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Zhejiang University, Hangzhou 310058, China.
authors.forename: Su
authors.initials: S
authors.lastname: Zeng
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000107:Acetylation; D010131:Aminosalicylic Acid / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000636:Aminosalicylic Acids / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D001711:Biotransformation; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002199:Capillary Permeability; D004285:Dogs; D007275:Injections, Intravenous; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D049990:Membrane Transport Modulators / Q000494:pharmacology; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014018:Tissue Distribution; D014162:Transfection
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D010131:Aminosalicylic Acid; D000636:Aminosalicylic Acids; D049990:Membrane Transport Modulators; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C086759:acetyl 4-aminosalicylic acid; C095122:multidrug resistance protein 3; C421109:multidrug resistance-associated protein 1