title: In vitro metabolism of dexamethasone cipecilate, a novel synthetic corticosteroid, in human liver and nasal mucosa.
abstract: Dexamethasone cipecilate (DX-CP, 9-fluoro-11β,17,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione 21-cyclohexanecarboxylate 17-cyclopropanecarboxylate) is a novel synthetic corticosteroid used to treat allergic rhinitis. The pharmacological effect of DX-CP is considered to be mainly due to its active de-esterified metabolite (DX-17-CPC). To investigate the in vitro metabolism of DX-CP in human liver, DX-CP was incubated with human liver microsomes and S9. In addition, a metabolism study of DX-CP with human nasal mucosa was carried out in order to elucidate whether DX-17-CPC is formed in nasal mucosa, the site of action of DX-CP. DX-17-CPC was the major metabolite in both liver microsomes and S9. Two new epoxide metabolites, UK1 and UK2, were detected in liver S9, while only UK1 was detected in liver microsomes. This suggests that cytosol enzymes are responsible for the formation of UK2. In human nasal mucosa, DX-CP was mainly transformed into DX-17-CPC. By using recombinant human carboxylesterases (CESs), the reaction was shown to be catalyzed by CES2. These results provide the evidence that the active metabolite DX-17-CPC is the main contributor to the pharmacological action after the intranasal administration of DX-CP to humans.
authors.affiliation: Discovery Research Laboratories, Nippon Shinyaku Co, Ltd, Nishinosho-Monguchi-Cho, Minami-ku, Kyoto, Japan. t.sasagawa@po.nipponshinyaku.co.jp
authors.forename: Takahiro
authors.initials: T
authors.lastname: Sasagawa
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Yamada
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Tomoo
authors.initials: T
authors.lastname: Tsujioka
authors.forename: Yousuke
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Naoko
authors.initials: N
authors.lastname: Kawakita
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Nonaka
authors.forename: Akio
authors.initials: A
authors.lastname: Nakamura
mesh_terms: D006801:Humans; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D009297:Nasal Mucosa / Q000201:enzymology / Q000378:metabolism*; D011282:Pregnenediones / Q000737:chemistry / Q000378:metabolism*
chemical_list: C552085:9-fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione 21-cyclohexanecarboxylate 17-cyclopropanecarboxylate; D011282:Pregnenediones