Combined oral cyclosporin and methotrexate therapy in patients with rheumatoid arthritis elevates methotrexate levels and reduces 7-hydroxymethotrexate levels when compared with methotrexate alone.
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.


CONCLUSIONS
CSA may block oxidation of MTX to its relatively inactive metabolite, 7-OH-MTX, thereby potentiating MTX efficacy.
Division of Rheumatology, Scripps Memorial Hospital and Research Foundation, La Jolla, California, USA.
R I
RI
Fox
S L
SL
Morgan
H T
HT
Smith
B A
BA
Robbins
M G
MG
Choc
J E
JE
Baggott
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000032:analysis / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000652:urine; D008875:Middle Aged
D007166:Immunosuppressive Agents; D016572:Cyclosporine; C011864:7-hydroxymethotrexate; D008727:Methotrexate