Metabolic fate of alclometasone dipropionate in rats, rabbits, and mice. Metabolic products and pathway following subcutaneous administration

S Aoyama and K Kamata

Kanzakigawa Laboratory, Shionogi Research Laboratories, Shionogi & Co., Ltd., Japan.

The metabolic fate of alclometasone dipropionate (ADP or S-3460) has been studied in rats, rabbits, and mice, with consideration of their interspecies differences. Several reference compounds related to ADP were synthesized for the determination and identification of the metabolites. After sc administration of 14C-labeled ADP, the metabolites in plasma, bile, and urine were separated and analyzed using TLC-ARG (autoradiography) and HPLC in comparison with the reference compounds. The metabolites identified, fully or tentatively, by MS and 1H-NMR totaled 11. The metabolic transformations were: hydrolysis of the side chain esters, dehydrochlorination leading to the formation of delta 6-double bond, 6 beta-hydroxylation, 6 beta, 7 beta- epoxides from 6 beta-hydroxylated metabolites, side chain oxidation to 21-oic and 20-oic acids in the 6 beta-hydroxylated metabolites, and conjugation to glucuronides and sulfates. The metabolic pathway, postulated on the basis of the identified and quantitated metabolites, was a rapid hydrolysis of 21-ester of ADP to the corresponding alcohol, M-1, after systemic uptake. This M-1 was a main metabolite in plasma of animals studied, and due to its relatively longer life time in the media, it seemed to allow a variety of metabolism to occur, giving the oxidative and conjugative metabolites mentioned above.

Volume 18, Issue 4, pp. 409-417, 07/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics