Rheumatology Advance Access originally published online on April 16, 2003
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Rheumatology 2003; 42: 989-994
© 2003 British Society for Rheumatology
Combined oral cyclosporin and methotrexate therapy in patients with rheumatoid arthritis elevates methotrexate levels and reduces 7-hydroxymethotrexate levels when compared with methotrexate alone
Division of Rheumatology, Scripps Memorial Hospital and Research Foundation, La Jolla, California,
1 Departments of Nutrition Sciences and Medicine, University of Alabama at Birmingham, Birmingham, Alabama,
2 Novartis Pharmaceutical Corporation, East, Hanover,
3 Bayer Consumer Care Division, Morristown and
4 Aventis, Bridgewater, New Jersey, USA
Objective. To study the pharmacokinetics of methotrexate (MTX) plus cyclosporin A (CSA) in patients with rheumatoid arthritis (RA).
Methods. On day 1 of the study, patients with RA receiving stable doses of MTX had blood and urine levels of MTX and its metabolite 7-hydroxymethotrexate (7-OH-MTX) measured post oral dosing of the drug. MTX was then discontinued and CSA therapy was started on day 8. On day 20, blood levels of CSA and CSA metabolites were measured post drug dosing. On day 23, MTX therapy was restarted and levels of MTX, CSA and their metabolites were again measured as described above.
Results. In the 30 patients, coadministration of CSA and MTX led to a 26% increase in mean peak plasma MTX concentration (P < 0.01), an 18% increase in the mean plasma MTX concentration area under the curve (AUC, P=0.01) and an 80% decrease in plasma 7-OH-MTX AUC (P < 0.01). In 13 patients receiving a 10 mg MTX dose, CSA reduced urinary 7-OH-MTX excretion by 87% (P < 0.01) without altering MTX excretion. MTX did not alter the pharmacokinetics of CSA or its metabolites.
Conclusion. CSA may block oxidation of MTX to its relatively inactive metabolite, 7-OH-MTX, thereby potentiating MTX efficacy.
KEY WORDS: Methotrexate, 7-Hydroxymethotrexate, Cyclosporin A, Pharmacokinetics.
Correspondence to: J. E. Baggott, 326 Webb, Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294–3360, USA. E-mail: jwrainey{at}uab.edu
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