Travocort Mechanism of Action

Pharmacology: Pharmacodynamics: Isoconazole nitrate is for use in the treatment of superficial fungal diseases of the skin. It displays a very broad spectrum of antimicrobial action. It is effective against dermatophytes and yeasts, yeast-like fungi (including the causative organism of pityriasis versicolor) and molds, as well as against gram-positive bacteria in-vitro and against the causative organism of erythrasma.
Diflucortolone valerate suppresses inflammation in inflammatory and allergic skin conditions and alleviates the subjective complaints such as pruritus, burning and pain.
Pharmacokinetics: Isoconazole nitrate: Isoconazole penetrates rapidly into human skin from Travocort cream and reaches maximum drug concentrations in the horny layer and in the living skin already 1 hour after application.
After topical application to rabbits higher levels antimycotic concentrations were obtained in the skin as compared to the corticosteroid-free preparation. This was interpreted as a retardation of percutaneous absorption of isoconazole nitrate as consequence of the vasoconstricitive effect of the corticosteroid.
Furthermore, the concentration ratio between antimycotic and corticosteroid in the skin is increased as compared to a ratio of 10:1 present in the Travocort cream, indicating that antimycotic efficacy is not impaired by the corticosteroid.
Isoconazole is not metabolically inactivated in the skin.
Systemic load due to percutaneous absorption is low. Even after removal of the horny layer less than 1% of the applied dose has reached the systemic circulation within 4 hours exposure time.
The percutaneous absorbed portion was too low to investigate the fate of isoconazole nitrate within the human organism. Therefore 0.5 mg of ³H-labeled isoconazole nitrate was injected intravenously. Isoconazole is completely metabolized and rapidly eliminated.
2,4-dichloromadelic acid and 2-(2,6-dichlorobenzyloxy)-2-(2,4-dichlorophenyl)-acetic acid were characterized as quantitatively most important metabolites. A third of the labeled substances was excreted with the urine and two thirds with the bile. 75% of the total dose was already excreted within 24 hours.
Diflucortolone valerate: Isoconazole dose not influence penetration and percutaneous absorption of diflucortolone valerate. Diflucortolone valerate penetrates rapidly into the skin leading to horny layer levels of approximately 150 μg/ml(=300 μmol/l) after one hour. Those levels are maintained for at least seven hours. Corticosteroid levels in the deeper epidermis were about 0.15 μg/ml (=0.3 μmol/l).
Diflucortolone valerate is partly hydrolyzed in the skin to the likewise effective diflucortolone. The portion of the corticosteroid, which is percutaneously absorbed, is low. Within four hour exposure time, less than 1% of the topically applied Travocort dose have been percutaneously absorbed.
Entering the systemic circulation, diflucortolone valerate is hydrolyzed to diflucortolone and the corresponding fatty acid within minutes. Besides diflucortolone 11-keto-diflucortoloneand two further metabolites have been detected in the plasma. Diflucortolone respectively all metabolites are eliminated from the plasma with half-lives of 4-5 hours and approx. 9 hours respectively (half-lives after i.v. injection) and are excreted in a ratio of 75:25 with urine and feces.