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Topical methotrexate: percutaneous penetration and clinical efficacy Wallace, Sylvia Mary Gloria


Because of the effectiveness of systemically administered methotrexate (MTX) in psoriasis, topical application of the drug has been suggested as a possible therapeutic regimen for the disease. However, controversy reigns over the clinical efficacy of such topical therapy and little is known of the absorption kinetics of topically applied MTX. In the present work percutaneous penetration of MTX was investigated in vitro and in vivo using hairless mouse and human skin. Clinical efficacy of topically applied and intralesionally injected MTX was tested in psoriatic patients. An unsuccessful attempt was made to isolate and obtain kinetic data for dihydro-folate reductase, the proposed target enzyme for MTX inhibition, in human skin. However, estimates of kinetic parameters for partially purified dihydrofolate reductase from chicken liver acetone powder are reported and are in agreement with literature values. In vivo topically applied MTX was rapidly absorbed through hairless mouse skin but not through the skin of psoriatic patients. In mice, topically applied MTX was detected by fluorometric analysis in the plasma and liver in amounts comparable to those obtained after intraperitoneal administration. Skin levels were also analyzed. Following topical application in psoriatic patients, MTX could be detected in neither plasma nor skin. In vitro, tritiated MTX penetrated through excised samples of hairless mouse and human autopsy skin at comparable rates when analyzed using liquid scintillation counting techniques. Vehicle pH affected steady state penetration rates. As pH of the suspension vehicle was increased from 3.49 to 8.15, and thus ionization of the weakly acidic MTX, steady state penetration rates decreased. Changes in penetration rates were correlated with changes in solubility and octanol-water partition coefficient as determined spectrophotometrically. Increasing the concentration of MTX in cream and suspension vehicles increased the penetration rates but not the concentration of MTX within the skin. Levels of MTX reached in vitro in hairless mouse skin were within the same range as those reached in vivo. In 17 out of 18 psoriatic patients topically applied (0.2% cream or 5 mg MTX deposited on the skin from an alcohol suspension) or intralesionally injected (0.5 mg) MTX was clinically ineffective. Any changes in the treated areas which suggested clinical improvement in the psoriatic lesions were paralleled by similar changes in control areas. Apparently, neither lack of percutaneous penetration nor low serum folate is the determining factor for activity of topical MTX. Evidence suggests that the site of action of MTX in psoriasis involves tissues other than the affected skin.

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