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Comparison of intracellular methotrexate kinetics in red blood cells with the kinetics in other cell types
Author(s) -
Korell Julia,
Duffull Stephen B.,
Dalrymple Judith M.,
Drake Jill,
Zhang Mei,
Barclay Murray L.,
Stamp Lisa K.
Publication year - 2014
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12209
Subject(s) - kinetics , intracellular , methotrexate , rheumatoid arthritis , pharmacokinetics , pharmacology , red blood cell , chemistry , immunology , medicine , biochemistry , physics , quantum mechanics
Aim 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 ( MTXG lu 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 10 mg oral MTX once weekly and the predicted steady‐state concentrations ( C ss ) and time to C ss ( t ss ) were compared. Results The HBCC model showed a lower C ss for MTXG lu 2 and 3 and higher C ss for MTXG lu 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 MTXG lu 1 and of t ss for all MTXG lu n , as well as a much lower cumulative C ss for MTXG lu 2–7 for the majority of the WBC cell lines. Conclusion 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.