Studies on the Metabolic Fate of Betamethasone Butyrate Propionate. (V). Metabolism and protein binding in rats and rabbits.

Abstract

The metabolism of 3H-betamethasone butyrate propionate (BBP) in male rats and rabbits was studied after dermal application. Plasma protein binding was also investigated.Except in epidermis and dermis, the unchanged BBP was not detected in any of studied specimen.1. Dermal metabolites High ratios of unchanged BBP as 70 ?? 80% of radioactivity were observed in both epidermis and dermis of the topical skin of rats at 24hr after the application. The major metabolites were BM-17•B in both tissues and BM-21•B in epidermis.2. Plasma metabolites The main metabolites in plasma were BM-17•B and BM-21•B, and the ratio of those decreased with time. On the other hand, the ratio of BM increased with time and it reached the highest 6hr after the application. After the repeated dosing, the main metabolite in plasma was BM, and the composition of the metabolites was similar to that after single dosing. In rabbits, the main metabolite in plasma was BM-17•B, and the ratio of BM-21•B was lower than that in rats.3. Metabolites in liver and kidney The major metabolites in rat liver and kidney were BM-17•B-6-OH, BM-17•B and BM. Many kinds of minor unknown metabolites were also detected in both organs.4. Urinary metabolies In rat urine, unknown metabolites U7, U8, U9, U11 and many minor metabolites including BM-17•B-6•OH, BM-6•OH, BM were detected. The similar composition was observed after the repeated dosing. In rabbit urine, unknown metabolites RU5, RU2 and many minor metabolites including BM-6•OH and BM were detected. After enzymatic hydrolysis of rabbit urine, increase of BM ratio was observed.5. Fecal metabolites In rabbit feces, BM-6•OH and BM were observed as the major metabolites.6. Plasma protein binding The in vivo plasma protein binding ratios of BBP after subcutaneous administration to rats were 86.4, 86.7and 59.7% at 1, 4 and 24hr, respectively. Those in vitro were as high as more than 97% both in case of rat and human plasma. Both ketotifen fumalate and chlorpheniramine maleate did not affect the in vitro bindings of BBP to rat and human plasma.