THE EFFECT OF METHOTREXATE AND 7-HYDROXYMETHOTREXATE ON RAT ADJUVANT ARTHRITIS AND ON URINARY AMINOIMIDAZOLE CARBOXAMIDE EXCRETION

Objective, To study the efficacy, toxicity, and antifolate activities of 7-hydroxymethotrexate (7-OH-MTX) versus methotrexate (MTX) in the t reatment of rat adjuvant-induced arthritis. Methods. Dose-dependent ef fects in rat adjuvant arthritis were determined by histologic and clin ical examinations. Antifolate activity was determined by urinary level s of aminoimidazole carboxamide (AIC) as a marker for blockade of the folate-dependent enzyme, aminoimidazolecarboxamide ribotide transformy lase (AICARTase). Results. MTX was 8 times more efficacious than 7-OH- MTX and resulted in higher urinary AIC levels. Increased urinary AIC l evels were correlated with suppression of rat adjuvant arthritis regar dless of the drug or dose level used. Conclusion. The ability to metab olize MTX to 7-OH-MTX and the sensitivity of AICARTase to inhibition b y 7-OH-MTX may at least partially account for the variability in respo nse to MTX. Blocking of AICARTase may be important in the efficacy of these antifolates.