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PERCUTANEOUS ABSORPTION AND DISPOSITION STUDIES OF METHOTREXATE IN RABBITS AND RATS
Author(s) -
LU GUANGWEI,
JUN H. WON,
SUH HEARAN
Publication year - 1997
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/(sici)1099-081x(199707)18:5<409::aid-bdd28>3.0.co;2-b
Subject(s) - methotrexate , chemistry , synovial fluid , pharmacology , pharmacokinetics , rheumatoid arthritis , stratum corneum , absorption (acoustics) , transdermal , arthritis , medicine , endocrinology , pathology , osteoarthritis , physics , alternative medicine , acoustics
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 ∼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 μg 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 (∼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 ∼87% was used for the quantitation of MTX in the tissue and fluid samples. © 1997 John Wiley & Sons, Ltd.