In vitrometabolism 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.

Identification of Drug Targets and Potential Molecular Mechanisms of Wantong Jingu Tablet in Treatment of Rats with Collagen-Induced Arthritis based on 16S rDNA High-Throughput Sequencing and Metabolomic Analysis

“…3'-N-debenzoyl-2'-deoxytaxol, dexamethasone cipecilate, tubulysin B, magnoline, and hydrocortisone valerate were another ve metabolites identi ed by correlation analysis, which were prominently reversed by WJT in CIA rats. Dexamethasone cipecilate characterized by increasing lipophilicity and enhancing pharmacological action has been identi ed as an effective therapy for allergic rhinitis [30]. Magnoline, an anti-inflammatory compound, has ability to inhibit the proliferation of cancer cells [31,32].…”

Identification of drug targets and potential molecular mechanisms of Wantong Jingu Tablet in treatment of rats with collagen-induced arthritis based on 16S rDNA high-throughput sequencing and metabolomic analysis

“…3'-N-debenzoyl-2'-deoxytaxol, dexamethasone cipecilate, tubulysin B, magnoline, and hydrocortisone valerate were another ve metabolites identi ed by correlation analysis, which were prominently reversed by WJT in CIA rats. Dexamethasone cipecilate characterized by increasing lipophilicity and enhancing pharmacological action has been identi ed as an effective therapy for allergic rhinitis [31]. Magnoline, an anti-in ammatory compound, has ability to inhibit the proliferation of cancer cells [32,33].…”

“…One hundred and twenty female speci c pathogen free (SPF) Sprague-Dawley (SD) rats weighing 160 to 180 g were obtained from Changchun Yisi Experimental Animal Technology Company. The rats were randomly assigned to six groups (G1, G2, G3, G4, G5, and G6), fasted for 12 h, but with free access to drinking water, before a single administration of 1 g (G1), 2 g (G2), 3.98 g (G3), 7.94 g (G4), 15.85 g (G5), 31.62 g (G6) of WJT power per kg of body weight. Signs of toxicity were evaluated based on mortality.…”

Cytochrome P450-mediated drug metabolizing activity in the nasal mucosa

“…Several isoforms of CYP450 monooxygenases were identified in the porcine nasal olfactory and respiratory mucosa, and the olfactory mucosa was observed to exhibit significantly higher CYP2A-mediated catalytic activities than those in the liver 66 (pig nasal and hepatic enzymes 76 . Nasal carboxylesterases have been reported to significantly metabolize drugs containing carboxylic acid esters as functional groups 80,81 . The importance of nasal esterases in modulating pharmacokinetics and pharmacological response of drugs was illustrated by ciclesonide, which is activated by nasal mucosal carboxylesterases and cholinesterases to active metabolite desisobutyryl-ciclesonide 82,83 .…”