Systemic and intestinal pharmacokinetics of methotrexate in patients with inflammatory bowel disease

Abstract

Subcutaneous methotrexate was well absorbed and distributed to the site of the lesions in patients with inflammatory bowel disease. Methotrexate was concentrated intracellularly in blood and in the rectum. The methotrexate concentration in the rectal mucosa remained within a pharmacologically active range throughout the dosing interval. The findings represent a pharmacologic explanation for the sustained efficacy of weekly methotrexate therapy.

Early Postoperative Complications are not Increased in Patients with Crohn's Disease Treated Perioperatively with Infliximab or Immunosuppressive Therapy

“…No minimum dose of AZA, 6MP, or MTX was required for inclusion in the study, because in clinical practice, the dose of immunosuppressive therapy with these medications is impacted by multiple factors including thiopurine methyltransferase enzyme activity, dose-dependent toxicity, and physician preference (8). The 1-month washout period for AZA, 6MP, and MTX was chosen based on the pharmacokinetics for the active metabolites of these medications: the erythrocyte concentration of 6-thioguanine nucleotides in patients treated with AZA or 6MP plateaus at 2-3 wk (9, 10); similarly, the erythrocyte concentration of methotrexate polyglutamate plateaus over 4-8 wk (11,12). The 8-wk washout period for infliximab before surgery was also chosen based on the pharmacokinetics of infliximab: the half life for infliximab in patients with CD is 8-10 days, and most patients treated with 5 mg/kg have detectable concentrations of the antibody at 8 wk, but not at 12 wk (13,14).…”

Clinical outcome and pharmacokinetics after addition of low-dose cyclosporine to methotrexate: A case study of five patients with treatment-resistant inflammatory bowel disease

“…Methotrexate was continued at 25 rnglweek by S.C. injection, and erythrocyte methotrexate, plasma methotrexate, and plasma 7-hydroxymethotrexate were measured every 2 weeks. The methotrexate assay methodologies have previously been described (24). The Inflammatory Bowel Disease Questionnaire (IBDQ) (25) was determined at baseline and every 2 weeks to monitor clinical disease activity.…”

“…Over 90% of a dose of subcutaneous methotrexate is eliminated unchanged in the urine (24). Because cyclosporine decreases glomerular filtration rate, we hypothesised that methotrexate blood levels would increase after addition of cyclosporine.…”

Increasing Systemic Exposure of Methotrexate by Active Efflux Mediated by Multidrug Resistance-Associated Protein 3 (Mrp3/Abcc3)

“…Methotrexate (N-{4-[(2,4-diaminopteridin-6-ylmethyl)-(methyl)amino]benzoyl}-L-glutamic acid), an inhibitor of dihydrofolate reductase, has been used clinically to treat neoplastic and autoimmune diseases including rheumatoid arthritis and psoriasis. Methotrexate is well absorbed from the small intestine into the systemic circulation (Tracy et al, 1994) followed by excretion into the urine in the unchanged form in humans (Egan et al, 1999). The accumulated evidence thus far suggests that multiple transporters are involved in the disposition of methotrexate.…”