title: Percutaneous absorption and disposition studies of methotrexate in rabbits and rats.
abstract: 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.
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Georgia, Athens 30602, USA.
authors.forename: G
authors.initials: G
authors.lastname: Lu
authors.forename: H W
authors.initials: HW
authors.lastname: Jun
authors.forename: H
authors.initials: H
authors.lastname: Suh
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D003671:DEET / Q000494:pharmacology; D004347:Drug Interactions; D004431:Ear, External / Q000187:drug effects / Q000378:metabolism; D006207:Half-Life; D007302:Insect Repellents / Q000494:pharmacology; D008727:Methotrexate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D012869:Skin Absorption / Q000187:drug effects / Q000502:physiology*; D013582:Synovial Fluid / Q000187:drug effects / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D000964:Antimetabolites, Antineoplastic; D007302:Insect Repellents; D003671:DEET; D008727:Methotrexate