Pharmacokinetics and biotransformation following topical use of the local corticoid prednicarbate

Kellner, H.M.; Eckert, H.G.; Fehlhaber, H.W.; Hornke, I.; Oekonomopulos, R.

Zeitschrift für Hautkrankheiten 61(Suppl 1): 18-40


ISSN/ISBN: 0301-0481
PMID: 3705671
Document Number: 4445
Studies on absorption and distribution in both skin and organism, as well as on elimination and biotransformation were performed in rats, pigs, and rabbits following topical application of the corticoid prednisolone-17-ethyl carbonate-21-propionate (prednicarbate; test name: Hoe 777), which had been labeled with 14C in position 4 for this purpose. After allowing the 0.25% greasy ointment to take effect for 6 hours, about half of the dose applied to rats and three quarters of that applied to pigs could be removed from the application area (rejection rate). Measurable blood levels, which could only be continuously determined in rats, initially occurred 0.5 to three hours after application; they remained very low throughout the experiment and finally reached concentrations between 0.007 and 0.012 micrograms equivalents of prednicarbate per ml 24 hours after administration. The excretion rate was 5 to 6% of the dose applied to rats and maximally 1.9% in pigs. In rats, the absorption after dermal application on an average amounted to 14% in healthy skin and to 22% in abraded skin. In pigs, we received values of about 1% and 4%, respectively. Allowing for species-related differences, the low quantity of absorption was also proved in healthy skin of rats and rabbits by means of in vitro-studies. Thus the amount which had penetrated within 6 hours was 3.3% in the model of the isolated perfused rabbit ear and 0.3% in the penetration chamber model in rats. As adhesive tape strippings and histoautoradiographic studies revealed, the radioactivity was highest in the uppermost layers of the stratum corneum and fell with increasing depth of skin. Our studies demonstrated that the horny layer serves both as a reservoir and as a barrier for prednicarbate. Experimental impairment of the barrier function resulted in an increased amount of active substance penetrating through the skin. During its passage through the organism, prednicarbate is almost completely metabolized, its metabolic fate resembling largely the biotransformation pathway of prednisolone. Among the numerous biotransformation products (about 20-30), 20 beta F-20-dihydroprednisolone and 6 beta-hydroxy-20 beta F-20-dihydroprednisolone were identified as the quantitatively most important metabolites in rats. On the basis of our results, we assume that at the site of action - the skin - highly potent prednicarbate becomes more and more changed by biotransformation on its way into the organism; this process results in formation of numerous metabolites, probably accounting for the very low systemic effect of the compound.

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Pharmacokinetics and biotransformation following topical use of the local corticoid prednicarbate