Effect of food on the bioavailability of low‐dose methotrexate in patients with rheumatoid arthritis

Abstract

Objective. To evaluate the influence of food on the bioavailability of an oral dose of methotrexate in patients with rheumatoid arthritis.Methods. Methotrexate (15 mg) was given intravenously and orally, with or without a meal, to 10 patients. Blood samples were drawn at specific intervals to evaluate drug levels.Results. Food reduced the peak concentration, from a mean of 0.71 pmoleshiter to 0.49 pmoles/liter (P < 0.02), and slightly increased the time to peak concentration, from a mean of 1.3 hours to 2.0 hours. Bioavailability was highly variable (range 28-9470) but was not affected by food intake. Conclusion. Bioavailability of oral methotrexate shows marked interindividual variation but is not affected by the presence of food.Methotrexate, a potent inhibitor of dihydrofolate reductase, was introduced into human pharmacology as an antineoplastic agent. It is increasingly being employed at low doses (5-25 mg weekly) as a secondline drug for rheumatoid arthritis that has been refractory to corticosteroid therapy (1) the high doses typically given to combat malignant diseases (2). Relatively little is known about the pharmacokinetics of low doses of this agent (3-5). Oral doses of less than 30 mg/m2 of body surface have been shown to be well absorbed (2), but milk is known to affect the methotrexate absorption in children with leukemia (6).Only one published study has addressed the bioavailability of methotrexate in patients with rheumatoid arthritis (4). In that study, the bioavailability of an oral dose of methotrexate was highly variable, ranging from 4% to 191%. Whether food affects the bioavailability of low-dose methotrexate is unknown. Although oral administration of methotrexate could be desirable for patients with rheumatoid arthritis, therapeutic success depends on adequate absorption. We therefore studied the bioavailability of methotrexate, and whether it was influenced by food, in patients with rheumatoid arthritis. PATIENTS AND METHODSPatient population. The bioavailability of methotrexate was studied in 10 patients (5 men and 5 women) with classic rheumatoid arthritis (7). The patients had a mean 2 SD body weight of 69 1-11 kg (range 56-90) and were 58 5 8 (mean 2 SD) years old (range 45-66). Eight patients were taking nonsteroidal antiinflammatory agents, and 5 were taking prednisone. All medications were withheld the day of the study. No other concomitant drugs, in particular, no drugs known t o induce or inhibit the microsomal oxygenase system, were taken.All patients had normal renal and hepatic function, as determined by assessing plasma levels of creatinine, liver function tests, and galactose elimination capacity. Four patients had been taking methotrexate for more than 1 year and 4 for less than 2 weeks. The study was approved by the

Low-Dose Methotrexate: A Mainstay in the Treatment of Rheumatoid Arthritis

“…In the treatment of rheumatoid arthritis, the usual dose of methotrexate is in the range of 15 to 17.5 mg/week, although early studies utilized much lower doses and others have reported using higher doses. At the doses commonly used for the treatment of rheumatoid arthritis, the bioavailability of oral methotrexate varies considerably between individuals, but in general is in the range of 70%, and food does not significantly affect uptake of the drug (Fossa et al, 1988;Kozloski et al, 1992;Oguey et al, 1992;Jundt et al, 1993;Lebbe et al, 1994;Bannwarth et al, 1996). There is some evidence that at higher doses oral bioavailability declines, a phenomenon most likely due to the fact that uptake of methotrexate from the gastrointestinal tract is mediated by a saturable transporter, reduced folate carrier 1 ( RFC1 1 ) (Matherly and Goldman, 2003).…”

“…Both methotrexate and 7-hydroxymethotrexate are primarily excreted in the urine, although there is some biliary excretion. The half-life of methotrexate in the serum is in the range of 6 to 8 h after administration of the drug and is undetectable in the serum by 24 h (Fossa et al, 1988;Kozloski et al, 1992;Oguey et al, 1992;Jundt et al, 1993;Lebbe et al, 1994;Bannwarth et al, 1996). By decreasing glomerular filtration rate, nonsteroidal antiinflammatory drugs may increase the time required to eliminate methotrexate, although this interaction is of little clinical significance (Furst, 1995).…”

Western and Chinese Antirheumatic Drug-Induced T Cell Apoptotic DNA Damage Uses Different Caspase Cascades and Is Independent of Fas/Fas Ligand Interaction

“…However, much higher concentrations (the average maximum concentration is 700 nM) can be achieved temporarily after an oral dose of 15 mg (30,31). The serum concentration quickly drops from 700 to Ͻ100 nM within 12 h and then reaches 1 nM ϳ40 h after administration of the medication (30).…”

The absorption of low‐dose methotrexate in patients with inflammatory bowel disease

“…13 Pinkerton et al 17 have shown that oral absorption of MTX can be substantially reduced by food; however, there are at least two studies which have demonstrated that bioavailability of the drug is largely independent of food intake. 18,19 To our knowledge, the effect of intestinal disease on MTX absorption has not been previously investigated, therefore, the main purpose of our study was to examine a possible impairment in the absorption of MTX in patients with IBD. We did not perform a complete bioavailability study for 24 h, but, since all patients had normal liver and kidney functions, we may assume that the bioavailability of MTX in all the patient groups was similar.…”