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Factors affecting human percutaneous penetration of methotrexate and its analogues in vitro
Abstract:
Factors affecting the percutaneous penetration of methotrexate (MTX) and its analogues through excised human skin were studied. With application of 0.05% MTX solution to the epidermis, 0.07% of the applied dose was recovered in the epidermis and less than 0.005% penetrated completely through the skin. The percent of drug which penetrated remained constant from 0.05% to 2.0% MTX and was also unchanged by increasing incubation temperature from 28 degrees C to 37 degrees C. Cellophane tape stripping of stratum corneum following drug incubation removed essentially all the MTX that had been measured in whole epidermis. Binding of MTX was localized to the outermost layers of the stratum corneum. With removal of the stratum corneum prior to drug incubation, 25% of the applied MTX penetrated through the skin. Various vehicles were tested to determine their effect on MTX percutaneous absorption. Dimethylsulfoxide (80%), dimethylacetamide (25%), or retinoic acid (0.1%) had no effect on penetration. Maximum enhancement of penetration by 25-fold and 143-fold was obtained with retinoic acid (saturated solution in aqueous ethanol) and C-10-methylsulfoxide (2.5%), respectively. The penetration of lipid-soluble derivatives of MTX was also tested. The compound that penetrated best was the dimethyl ester of dichloro-MTX with a 3-fold increase in penetration over MTX.
Insights
Methotrexate (MTX) penetration through human skin is minimal, primarily binding to the stratum corneum. Enhancing MTX absorption requires specific vehicles like C-10-methylsulfoxide or lipid-soluble derivatives.
Area of Science:
- Dermatology
- Pharmacokinetics
- Drug Delivery
Background:
- Percutaneous absorption is crucial for topical drug efficacy.
- Methotrexate (MTX) is a chemotherapy agent with potential for topical use.
- Understanding MTX skin penetration is key for optimizing dermatological treatments.
Purpose of the Study:
- To investigate factors influencing percutaneous penetration of methotrexate (MTX) and its analogues through human skin.
- To evaluate the impact of concentration, temperature, and stratum corneum on MTX absorption.
- To identify vehicles and MTX derivatives that enhance skin penetration.
Main Methods:
- Excised human skin samples were used to study MTX penetration.
- Varying concentrations of MTX and incubation temperatures were applied.
- Stratum corneum removal and tape stripping were employed.
- Different vehicles and MTX analogues were tested for their effect on absorption.
Main Results:
- Less than 0.005% of applied MTX penetrated intact human skin; most bound to the stratum corneum.
- Penetration remained constant across MTX concentrations (0.05%-2.0%) and temperatures (28°C-37°C).
- Removing the stratum corneum increased penetration to 25%; C-10-methylsulfoxide (2.5%) and retinoic acid (saturated) enhanced penetration 143-fold and 25-fold, respectively.
- The dimethyl ester of dichloro-MTX showed a 3-fold increase in penetration over MTX.
Conclusions:
- MTX primarily accumulates in the stratum corneum, limiting systemic absorption.
- Stratum corneum integrity is a major barrier to MTX percutaneous penetration.
- Specific chemical enhancers and lipid-soluble MTX derivatives show potential for improving topical drug delivery.