Methotrexate catabolism to 7-hydroxymethotrexate in rheumatoid arthritis alters drug efficacy and retention and is reduced by folic acid supplementation.
OBJECTIVE
To assess the catabolism of methotrexate (MTX) to 7-hydroxy-MTX (7-OH-MTX) in patients with rheumatoid arthritis as well as the effect of folic acid and folinic acid on this catabolism.


METHODS
Urinary excretion of MTX and its catabolite, 7-OH-MTX, was measured in 2 24-hour urine specimens collected after MTX therapy. Urine samples were collected from patients after the sixth and seventh weekly doses of MTX. MTX and 7-OH-MTX concentrations were determined by high-performance liquid chromatography mass spectrometry. Swelling and pain/tenderness indices were used to measure symptoms before and at 6 and 7 weeks of therapy. Patients received either folic acid or folinic acid supplements (1 mg/day) from week 6 to week 7.


RESULTS
Folic acid inhibited aldehyde oxidase (AO), the enzyme that produces 7-OH-MTX, but folinic acid did not. Excretion of 7-OH-MTX (determined as a percentage of the dose of MTX or as mg 7-OH-MTX/gm creatinine) was not normally distributed (n=39). Patients with marked improvement in swelling and pain/tenderness indices had a lower mean 7-OH-MTX excretion level (P<0.05). Patients who received folic acid supplements had decreased 7-OH-MTX excretion (P=0.03). Relatively high 7-OH-MTX excretion was correlated with relatively high MTX excretion and with relatively low MTX retention in vivo (P<0.05) (n=35).


CONCLUSIONS
Our findings of a non-normal distribution of 7-OH-MTX excretion suggest that there are at least 2 phenotypes for this catabolism. Decreased 7-OH-MTX formation suggests folic acid inhibition of AO and a better clinical response, while increased 7-OH-MTX formation may interfere with MTX polyglutamylation and binding to enzymes and, therefore, may increase MTX excretion and decrease MTX retention and efficacy in vivo.
Baggott
Joseph E
JE
University of Alabama at Birmingham, Birmingham, AL 35294-1270, USA.
Morgan
Sarah L
SL
D042931:Aldehyde Oxidase / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002851:Chromatography, High Pressure Liquid; D005492:Folic Acid / Q000008:administration & dosage*; D006304:Health Status; D006801:Humans; D007596:Joints / Q000503:physiopathology; D002955:Leucovorin / Q000008:administration & dosage; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use* / Q000652:urine; D010146:Pain / Q000188:drug therapy / Q000503:physiopathology; D053719:Tandem Mass Spectrometry / Q000379:methods; D016896:Treatment Outcome
D005492:Folic Acid; D042931:Aldehyde Oxidase; D002955:Leucovorin; C011864:7-hydroxymethotrexate; D008727:Methotrexate