The effect of methotrexate and 7-hydroxymethotrexate on rat adjuvant arthritis and on urinary aminoimidazole carboxamide excretion.

Academic Article

Abstract

  • OBJECTIVE: To study the efficacy, toxicity, and antifolate activities of 7-hydroxymethotrexate (7-OH-MTX) versus methotrexate (MTX) in the treatment of rat adjuvant-induced arthritis. METHODS: Dose-dependent effects in rat adjuvant arthritis were determined by histologic and clinical examinations. Antifolate activity was determined by urinary levels of aminoimidazole carboxamide (AIC) as a marker for blockade of the folate-dependent enzyme, aminoimidazolecarboxamide ribotide transformylase (AICARTase). RESULTS: MTX was 8 times more efficacious than 7-OH-MTX and resulted in higher urinary AIC levels. Increased urinary AIC levels were correlated with suppression of rat adjuvant arthritis regardless of the drug or dose level used. CONCLUSION: The ability to metabolize MTX to 7-OH-MTX and the sensitivity of AICARTase to inhibition by 7-OH-MTX may at least partially account for the variability in response to MTX. Blocking of AICARTase may be important in the efficacy of these antifolates.
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    Keywords

  • Aminoimidazole Carboxamide, Animals, Arthritis, Experimental, Dose-Response Relationship, Drug, Female, Folic Acid Antagonists, Hindlimb, Hydroxymethyl and Formyl Transferases, Joints, Methotrexate, Phosphoribosylaminoimidazolecarboxamide Formyltransferase, Rats, Rats, Inbred Lew
  • Author List

  • Baggott JE; Morgan SL; Koopman WJ
  • Start Page

  • 1407
  • End Page

  • 1410
  • Volume

  • 41
  • Issue

  • 8