PERCUTANEOUS ABSORPTION AND DISPOSITION STUDIES OF METHOTREXATE IN RABBITS AND RATS

✍ Scribed by GUANGWEI LU; H. WON JUN; HEARAN SUH

• Publisher: John Wiley and Sons
• Year: 1997
• Tongue: English
• Weight: 162 KB
• Volume: 18
• Category: Article
• ISSN: 0142-2782
• DOI: 10.1002/(sici)1099-081x(199707)18:5<409::aid-bdd28>3.0.co;2-b

✦ Synopsis

The absorption and disposition of methotrexate (MTX) in the plasma, synovial fluid (SF), skin, and muscle tissue were studied following administration of a topical MTX gel in rabbits and rats. In rabbits, MTX concentrations in the plasma increased steadily toward the peak (5.9 +/- 2.8 ng mL-1) which appeared at approximately 2 h postdose and declined with the elimination half-life of 4.48 +/- 1.74 h. At 1 h after the topical dose, the MTX concentrations in the skin (49.0 +/- 19.8 micrograms g-1), muscle (12.7 +/- 3.3 ng g-1), and SF (19.2 +/- 10.1 ng g-1) underneath the dosed stifle joint were significantly higher (p < 0.05) than those of the untreated stifle joint, indicating the potential therapeutic value of topical delivery of MTX for rheumatoid arthritis. A large fraction (approximately 59%) of MTX which was found in the skin at 1 h postdose was present in the stratum corneum, indicating its extensive 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 higher than those in the dosed elbow joint, respectively, reflecting the effect of dose site on the permeation of MTX. Using a new filter paper 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 linear calibration curve (r > 0.999) over the range of 2-50 ng mL-1. quantitation limit of 0.5 ng mL-1, and mean recovery of approximately 87% was used for the quantitation of MTX in the tissue and fluid samples.