Comparison of intracellular methotrexate kinetics in red blood cells with the kinetics in other cell types

• AimTo assess the similarities in intracellular pharmacokinetics (PK) of methotrexate (MTX) in red blood cells (RBCs) and other cell lines. MethodsThree previously published PK models for intracellular MTX and MTX polyglutamate (MTXGlu(2-5)) 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 10mg oral MTX once weekly and the predicted steady-state concentrations (C-ss) and time to C-ss (t(ss)) were compared. ResultsThe HBCC model showed a lower C-ss for MTXGlu(2 and 3) and higher C-ss for MTXGlu(4 and 5) compared with the RBC PK model, while t(ss) and overall intracellular MTX exposure appeared similar. The WBC PK model showed much lower C-ss for the parent MTXGlu(1) and of t(ss) for all MTXGlu(n), as well as a much lower cumulative C-ss for MTXGlu(2-7) for the majority of the WBC cell lines. ConclusionRBC 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.

Keyword

cell lines

intracellular kinetics

methotrexate

polyglutamates

rheumatoid arthritis

simulations

Publication and Content Type

ref (subject category)

art (subject category)