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 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.


CONCLUSIONS
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.
University of Alabama at Birmingham, 35294, USA.
J E
JE
Baggott
S L
SL
Morgan
W J
WJ
Koopman
D000620:Aminoimidazole Carboxamide / Q000652:urine*; D000818:Animals; D001169:Arthritis, Experimental / Q000473:pathology* / Q000652:urine*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D006614:Hindlimb; D019877:Hydroxymethyl and Formyl Transferases / Q000037:antagonists & inhibitors; D007596:Joints / Q000473:pathology; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase; D051381:Rats; D011917:Rats, Inbred Lew
D005493:Folic Acid Antagonists; D000620:Aminoimidazole Carboxamide; D019877:Hydroxymethyl and Formyl Transferases; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase; C011864:7-hydroxymethotrexate; D008727:Methotrexate