1. Methotrexate for Inflammatory Bowel Disease: Pharmacology and Preliminary Results 
Laurence J. Egan, M.B., William J. Sandborn, M.D 
Mayo Clinic Proceedings 
Volume 71, Issue 1, Pages (January 1996)
DOI: /
Copyright © 1996 Mayo Foundation for Medical Education and Research Terms and Conditions

2. Fig. 1
Enzymes in metabolic pathway of folic acid inhibited by niethotrcxalc (MTX) therapy. MTX and its polyglutamate metabolites (MTXPG) potently inhibit dihydrofolate reductase (DHFR), impairing production of tctrahydrofolates (THE) and leading to accumulation and polyglutamation of dihydrofolate and oxidized folatcs (DHFPG). Polyglutamation of MTX confers greatly enhanced inhibitory activity against folate-dependent enzymes distal to DHFR, including thymidylate synthase (TS);7 the trifunctional enzyme 10-formyltetrahydrofolate synthetase, cyclohydrolase, dehydrogenase; and 5-aminoimidazole-4-carboxamide ribotide (AICAR) transformylase.8 In addition, DHFPG are potent inhibitors of some folate-dependent enzymes including TS, AICAR transformylase, and methionine synthetase (MS)8 Polyglutamate derivatives of another MTX metabolite, 7-hydroxymethotrexate (7-OH-MTXPG), also inhibit AICAR transformylase and probably other folate-dependent enzymes.9 Inhibition of AICAR transformylase leads to accumulation of AICAR, which, like MTXPG and DHFPG, leads to accumulation of adenosine, partly through inhibition of adenosine deaminase (ADA)} Therefore, net effects of MTX include inhibition of folate-dependent reactions involving transfer of one-carbon fragments such as production of thymidylate and purines, inhibition of production of methionine, and local accumulation of adenosine. DHF = dihydrofolate; dTMP = deoxythymidinc monophosphate; dUMP = deoxyuridine monophosphate; FPGS = folylpolyglutamate synthetase; IMP = inosine monophosphate; THFPG = tetrahydrofolate polyglutamate.
Mayo Clinic Proceedings  , 69-80DOI: ( / )
Copyright © 1996 Mayo Foundation for Medical Education and Research Terms and Conditions

3. Fig. 2
Plasma concentrations of methotrexate (MTX) and 7-hydroxymethotrexate (7-OH-MTX) after administration of single 15-mg dose by intravenous (IV), intramuscular (IM), and oral (PO) routes. (Modified from Seideman and associates.12 By permission.)
Mayo Clinic Proceedings  , 69-80DOI: ( / )
Copyright © 1996 Mayo Foundation for Medical Education and Research Terms and Conditions

4. Fig. 3
Serum aspartatc aminolransfcrase (AST) levels in patients with rheumatoid arthrilis after initiation of methotrexate treatment. SEM = standard error of mean. (Modified from Kremer JM, K.off R. A debate: should patients with rheumatoid arthritis on methotrexate undergo liver biopsies? Semin Arthritis Rheum 1992;21: By permission.)
Mayo Clinic Proceedings  , 69-80DOI: ( / )
Copyright © 1996 Mayo Foundation for Medical Education and Research Terms and Conditions