Koichi Sugeno

Binding affinities of mometasone furoate and related compounds including its metabolites for the glucocorticoid receptor of rat skin tissue

The binding affinities of mometasone furoate (MF), its metabolites and related compounds for the glucocorticoid receptor of rat epidermis and dermis were measured. MF and its main metabolite exhibited binding affinities higher than those of alclomethasone dipropionate (ADP) and betamethasone dipropionate (BDP), but equivalent to betamethasone 17-valerate (BMV). For compound I (metabolite of MF), ADP, BDP and BMV, the binding affinity was found to be higher in epidermis relative to dermis. This difference in the dermal/epidermal binding ratio may be a favorable sign leading to a possible reduction of dermal collagen atrophy, a known side effect of glucocorticoids. In structure-binding relationship studies, esterification of the 17-OH by furoylation and introduction of the 9 alpha-Cl caused a marked increase of the binding affinity, whereas the 6 beta-hydroxylation led to a pronounced decrease.

[Pharmacology of a new sleep-inducer, 1H-1,2,4-triazolyl benzophenone derivative, 450191-S (VI). Determination of metabolites in monkey plasma by combined high-performance liquid chromatography and enzyme immunoassay].

A new sleep-inducer, 450191-S, was orally administered to two old rhesus monkeys and three young ones at a pharmacologically active dose (1 mg/kg). The area under the plasma concentration versus time curve (AUC) of M-1 was the smallest among the measured metabolites. The AUC of M-2 in the old monkeys was 10 times higher than that of the young ones. M-A was one of the major metabolites, and its AUC in the old monkeys was also four times higher than that in the young ones. The AUC of M-3 was the largest among the measured metabolites. The time of maximum concentration was 12-16 hr after dosing; and thereafter, the concentration decreased gradually with a 12-hr half-life. The M-4 level was constantly low during 24 hr after dosing and then decreased gradually. The active metabolite M-1 was also administered to the two young monkeys at a dose of 0.73 mg/kg, and the time course of the plasma concentration of metabolites was compared with that after 450191-S administration to the young monkeys, because 450191-S may be changed to M-1 in the process of intestinal absorption. The concentration of M-1 was extremely low in spite of the dosing of M-1 itself, and the AUC of M-1 was one-sixth of that after 450191-S administration. The concentration of M-2 was also low, and its AUC was one-third of that after 450191-S administration. The AUCs of M-A, M-3 and M-4 were not very different from those after 450191-S administration. These results indicated that there is an age-related difference in the plasma concentration of M-2 and M-A when 450191-S is administered orally and that the plasma concentrations of M-1 and M-2 differ greatly between 450191-S and M-1 administrations.