title: Aclidinium bromide, a new, long-acting, inhaled muscarinic antagonist: in vitro plasma inactivation and pharmacological activity of its main metabolites.
abstract: 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 M(1) to M(5) 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, > or =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.
authors.affiliation: Almirall, R&D Center, Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Sentellas
authors.forename: Israel
authors.initials: I
authors.lastname: Ramos
authors.forename: Joan
authors.initials: J
authors.lastname: Albertí
authors.forename: Miquel
authors.initials: M
authors.lastname: Salvà
authors.forename: Francisca
authors.initials: F
authors.lastname: Antón
authors.forename: Montserrat
authors.initials: M
authors.lastname: Miralpeix
authors.forename: Jorge
authors.initials: J
authors.lastname: Beleta
authors.forename: Amadeu
authors.initials: A
authors.lastname: Gavaldà
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D006801:Humans; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D014326:Tropanes / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D018727:Muscarinic Antagonists; D014326:Tropanes; C542859:aclidinium bromide