title: Comparison of intracellular methotrexate kinetics in red blood cells with the kinetics in other cell types.
abstract: OBJECTIVE
  To assess the similarities in intracellular pharmacokinetics (PK) of methotrexate (MTX) in red blood cells (RBCs) and other cell lines.
  
  
  METHODS
  Three previously published PK models for intracellular MTX and MTX polyglutamate (MTXGlu2-5 ) concentrations were used: (i) a model for the kinetics in RBCs, (ii) a model for the kinetics in human breast cancer cells (HBCCs) and (iii) a model for the kinetics in various white blood cell (WBC) lines. All three models were used to simulate the response in a typical individual receiving 10 mg oral MTX once weekly and the predicted steady-state concentrations (Css ) and time to Css (tss ) were compared.
  
  
  RESULTS
  The HBCC model showed a lower Css for MTXGlu2 and 3 and higher Css for MTXGlu4 and 5 compared with the RBC PK model, while tss and overall intracellular MTX exposure appeared similar. The WBC PK model showed much lower Css for the parent MTXGlu1 and of tss for all MTXGlun , as well as a much lower cumulative Css for MTXGlu2-7 for the majority of the WBC cell lines.
  
  
  CONCLUSIONS
  RBC kinetics of MTX differ from the kinetics in other cell types such as WBCs and HBCCs to a variable degree. It is possible that similarly diverse profiles may exist across other cell lines, including those on the causal path in rheumatoid arthritis. Hence, there may not necessarily be a clear link between RBC MTX concentrations and disease control in rheumatoid arthritis.
authors.affiliation: School of Pharmacy, University of Otago, Dunedin, New Zealand; Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Julia
authors.initials: J
authors.lastname: Korell
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Duffull
authors.forename: Judith M
authors.initials: JM
authors.lastname: Dalrymple
authors.forename: Jill
authors.initials: J
authors.lastname: Drake
authors.forename: Mei
authors.initials: M
authors.lastname: Zhang
authors.forename: Murray L
authors.initials: ML
authors.lastname: Barclay
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Stamp
mesh_terms: D000284:Administration, Oral; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D003198:Computer Simulation; D004334:Drug Administration Schedule; D004912:Erythrocytes / Q000378:metabolism*; D005260:Female; D006801:Humans; D007700:Kinetics; D007962:Leukocytes / Q000378:metabolism*; D008727:Methotrexate / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics; D008954:Models, Biological; D011099:Polyglutamic Acid / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D018501:Antirheumatic Agents; D011099:Polyglutamic Acid; C014085:methotrexate polyglutamate; D008727:Methotrexate
keywords: cell lines; intracellular kinetics; methotrexate; polyglutamates; rheumatoid arthritis; simulations