Methotrexate (MTX), an antivitamin of folic acid (FA) is used in low doses for the treatment of rheumatoid arthritis (RA). Numerous trials have demonstrated that FA can lessen the toxicity of MTX for RA therapy without lessening efficacy. We hypothesize that supplemental FA can be administered in the same capsule as MTX, without altering the pharmacokinetic profile of MTX. Fifteen patients fulfilling the American College of Rheumatology's criteria for RA, who are currently taking MTX but not taking FA will be recruited. The subjects will be admitted to the General Clinical Research Center and will receive 7.5 mg of MTX and either 0, 15, or 37.5 mg of folic acid as a time-released preparation and act as his or her own control. Pharmacokinetic modeling and bioavailability assessments will be done. MTX levels will be measured by HPLC and FA by a microbiological MTX-resistant L. casei method. If MTX and FA can be coadministered, this provides important information about differential absorption and confirms that dihydrofolate reductase is not an important enzyme to target for the efficacy of MTX therapy. In addition, the coadministration of FA and MTX may make MTX a more useful drug by lowering toxicity and simplify drug therapy. PROPOSED COMMERCIAL APPLICATIONS: R & D Laboratories Inc. (R& D) believes that this investigation will lead to a combination product which will improve patient health and quality of life. Once data have been established regarding the use of folic acid in combination with methotrexate to mitigate toxicity, R & D expects that concomitant marketing research would be done to ascertain the commercial potential for this drug. R & D is committed to research regarding a commercial base and subsequent commercial development.