The pharmacokinetics of methotrexate and its 7‐hydroxy metabolite in patients with rheumatoid arthritis

1. The pharmacokinetics of MTX and its 7‐hydroxy metabolite (7‐OHMTX) were investigated in nine patients with rheumatoid arthritis (RA). Each patient received 15 mg MTX i.v., i.m. and p.o. after an overnight fast in a randomized cross‐over design. The plasma concentrations of MTX and 7‐OHMTX were measured over 7 days and their urinary excretion over 24 h. 2. Plasma concentrations of MTX were described by a triexponential function after i.v. administration, a triexponential function with zero or first order absorption after oral administration, and a biexponential function with zero of first order absorption after i.m. injection. Plasma concentrations of 7‐OHMTX were described by a biexponential function after all three routes of administration. The median terminal elimination half‐lives of MTX and 7‐OHMTX were 55 h and 116 h, respectively. The area under the plasma concentration‐time curve (AUC (0,170 h)) of MTX did not differ between i.m. and oral administration indicating similar bioavailability after these routes of administration. The AUC (0,170 h) values of 7‐OHMTX after i.v., oral and i.m. administration were similar. Over 80% of MTX was excreted in urine as intact drug and about 3% was excreted as 7‐OHMTX during 24 h after drug administration. 3. Plasma concentrations of MTX and 7‐OHMTX were measurable at the end of the dose interval in most of the patients and may help to identify non‐responders or patients with increased risk of side‐effects.