Aclidinium bromide, a new, long-acting, inhaled muscarinic antagonist: In vitro plasma inactivation and pharmacological activity of its main metabolites

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• 作者：Sonia Sentellas ; Israel Ramos ; Joan Albertí ; Miquel Salvà ; Francisca Antó ; n ; Montserrat Miralpeix ; Jorge Beleta ; Amadeu Gavaldà
• 关键词：Aclidinium bromide ; Plasma hydrolysis ; Plasma esterases ; Metabolites pharmacology
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2010
• 出版时间：18 March 2010
• 年：2010
• 卷：39
• 期：5
• 页码：283-290
• 全文大小：557 K

文摘

Aclidinium bromide is a novel, long-acting inhaled muscarinic antagonist drug in Phase III clinical trials for chronic obstructive pulmonary disease (COPD). The aims of this study were to evaluate the in vitro stability of the ester drug aclidinium in plasma from various species, and the in vitro and in vivo pharmacological activity of its hydrolysis metabolites. Following incubation of aclidinium in pooled samples of human, rat, guinea pig or dog plasma, the rate of hydrolysis was quantified by reversed phase ultra performance liquid chromatography and mass spectrometry. Tiotropium and ipratropium were used as comparators. The in vitro biochemical profile of the hydrolysis metabolites of aclidinium was assessed in human M₁ to M₅ muscarinic receptors and in a standard selectivity panel (85 G protein-coupled receptors [GPCRs], ion channels and enzymes). The bronchodilator activity of the metabolites of aclidinium bromide was studied in guinea pigs after acetylcholine-induced bronchoconstriction.

Aclidinium was rapidly hydrolysed into carboxylic acid and alcohol derivatives in guinea pig, rat, human and dog plasma with half-lives of 38, 11.7, 2.4 and 1.8 min, respectively. In contrast, ≥70 % of tiotropium and ipratropium remained unchanged in the plasma after 60 min of incubation. The carboxylic acid and alcohol metabolites had no significant affinity for any of the muscarinic receptors, other GPCRs, ion channels or enzymes studied and showed no relevant antibronchoconstrictory activity in vivo. These results suggest that aclidinium may have a reduced systemic exposure and therefore less propensity for class-related systemic side effects in the clinical setting.