title: Quantification of Four Efflux Drug Transporters in Liver and Kidney Across Species Using Targeted Quantitative Proteomics by Isotope Dilution NanoLC-MS/MS.
abstract: The expression levels of several efflux drug transporters in the liver and kidney were evaluated across species to address potential roles of the transporters in species dependent excretion of drugs and their metabolites.
  
  
  
  Four efflux transporters, namely MDR1/P-gp, BCRP/Bcrp, MRP2/Mrp2 and MRP3/Mrp3 in liver and kidney in three preclinical species and humans were quantified using targeted quantitative proteomics by isotope dilution nanoLC-MS/MS.
  
  
  
  In liver, the level of P-gp was highest in monkey and lowest in rat. The concentration of BCRP/Bcrp was highest in dog followed by monkey. MRP2/Mrp2 level was highest in monkey and rat, whereas MRP3/Mrp3 levels were similar in human, monkey and dog. In the kidney, the concentrations of MDR1/P-gp in human and monkey were roughly 2 to 3-fold higher than in rat and dog. In rat, BCRP/Bcrp concentrations were substantially higher than in any of the other species. MRP2/Mrp2 concentrations were similar across species, whereas expression of MRP3/Mrp3 was highest in rat.
  
  
  
  Overall, the results indicated that the pattern of hepatic and renal expression of the transporters was quite species dependent. This information should be helpful in the estimation of transport mediated drug and metabolites excretion in liver and kidney across species.
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA.
authors.forename: John K
authors.initials: JK
authors.lastname: Fallon
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Smith
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International Co., 40 Landsdowne Street, Cambridge, Massachusetts, 02139, USA.
authors.forename: Cindy Q
authors.initials: CQ
authors.lastname: Xia
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International Co., 40 Landsdowne Street, Cambridge, Massachusetts, 02139, USA. mi-sook.kim@takeda.com.
authors.forename: Mi-Sook
authors.initials: MS
authors.lastname: Kim
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D004285:Dogs; D005260:Female; D000882:Haplorhini; D006801:Humans; D007554:Isotopes / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry / Q000379:methods
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D007554:Isotopes; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D004364:Pharmaceutical Preparations
keywords: efflux; proteomics; quantitative; species; transporters