PERCUTANEOUS-ABSORPTION AND DISPOSITION STUDIES OF METHOTREXATE IN RABBITS AND RATS

The absorption and disposition of methotrexate (MTX) in the plasma, sy novial fluid (SF), skin, and muscle tissue were studied following admi nistration of a topical MTX gel in rabbits and rats. In rabbits, MTX c oncentrations in the plasma increased steadily toward the peak (5.9 +/ - 2.8 ng mL(-1)) which appeared at similar to 2 h postdose and decline d with the elimination half-life of 4.48 +/- 1.74 h. At 1h after the t opical dose, the MTX concentrations in the skin (49.0 +/- 19.8 mu g g( -1)), muscle (12.7 +/- 3.3 ng g(-1)), and SF (192 +/- 10.1 ng g(-1)) u nderneath the dosed stifle joint were significantly higher (p < 0.05) than those of the untreated stifle joint, indicating the potential the rapeutic value of topical delivery of MTX for rheumatoid arthritis. A large fraction (similar to 59%) of MTX which was found in the skin at Ih postdose was present in the stratum corneum, indicating its extensi ve binding capacity for MTX. The MTX concentrations in the muscle and SF of the dosed stifle joint at 1 h postdose were 1.8 and 2.6 times hi gher than those in the dosed elbow joint, respectively, reflecting the effect of dose site on the permeation of MTX. Using a new filter pape r method, the amounts of SF obtained from the elbow and stifle joints of four rabbits were 26.3 +/- 8.3 and 48.8 +/- 5.2 mg, respectively. A significant enhancer effect of N,N-diethyl-n-toluamide (DEET) on the disposition of MTX in the stratum corneum of rabbit ear was observed ( p < 0.05) by the tape-stripping method. In rats, the gel containing 4% DEET resulted in a twofold increase in the permeation of MTX into the muscle over the 4 h period postdose. A modified HPLC method with a li near calibration curve (r > 0.999) over the range of 2-50 ng mL(-1), q uantitation limit of 0.5 ng mL(-1), and mean recovery of similar to 87 % was used for the quantitation of MTX in the tissue and fluid samples . (C) 1997 by John Wiley & Sons, Ltd.