title: The in vitro and in vivo profile of aclidinium bromide in comparison with glycopyrronium bromide.
abstract: This study characterised the in vitro and in vivo profiles of two novel long-acting muscarinic antagonists, aclidinium bromide and glycopyrronium bromide, using tiotropium bromide and ipratropium bromide as comparators. All four antagonists had high affinity for the five muscarinic receptor sub-types (M1-M5); aclidinium had comparable affinity to tiotropium but higher affinity than glycopyrronium and ipratropium for all receptors. Glycopyrronium dissociated faster from recombinant M3 receptors than aclidinium and tiotropium but more slowly than ipratropium; all four compounds dissociated more rapidly from M2 receptors than from M3 receptors. In vitro, aclidinium, glycopyrronium and tiotropium had a long duration of action at native M3 receptors (>8 h versus 42 min for ipratropium). In vivo, all compounds were equi-potent at reversing acetylcholine-induced bronchoconstriction. Aclidinium, glycopyrronium and ipratropium had a faster onset of bronchodilator action than tiotropium. Aclidinium had a longer duration of action than glycopyronnium (time to 50% recovery of effect [t½ offset] = 29 h and 13 h, respectively); these compare with a t½ offset of 64 h and 8 h for tiotropium and ipratropium, respectively. Aclidinium was less potent than glycopyrronium and tiotropium at inhibiting salivation in conscious rats (dose required to produce half-maximal effect [ED50] = 38, 0.74 and 0.88 μg/kg, respectively) and was more rapidly hydrolysed in rat, guinea pig and human plasma compared with glycopyrronium or tiotropium. These results indicate that while aclidinium and glycopyrronium are both potent antagonists at muscarinic receptors with similar kinetic selectivity for M3 receptors versus M2, aclidinium has a longer dissociation half-life at M3 receptors and a longer duration of bronchodilator action in vivo than glycopyrronium. The rapid plasma hydrolysis of aclidinium, coupled to its kinetic selectivity, may confer a reduced propensity for systemic anticholinergic side effects with aclidinium versus glycopyrronium and tiotropium.
authors.affiliation: Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain. Electronic address: amadeu.gavalda@almirall.com.
authors.forename: Amadeu
authors.initials: A
authors.lastname: Gavaldà
authors.affiliation: Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain. Electronic address: israel.ramos@almirall.com.
authors.forename: Israel
authors.initials: I
authors.lastname: Ramos
authors.affiliation: Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain. Electronic address: carla.carcasona@almirall.com.
authors.forename: Carla
authors.initials: C
authors.lastname: Carcasona
authors.affiliation: Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain. Electronic address: elena.calama@almirall.com.
authors.forename: Elena
authors.initials: E
authors.lastname: Calama
authors.affiliation: Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain. Electronic address: raquel.otal@almirall.com.
authors.forename: Raquel
authors.initials: R
authors.lastname: Otal
authors.affiliation: Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain. Electronic address: jose.luis.montero@almirall.com.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Montero
authors.affiliation: Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain. Electronic address: sonia.sentellas@almirall.com.
authors.forename: Sonia
authors.initials: S
authors.lastname: Sentellas
authors.affiliation: Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain. Electronic address: monica.aparici@almirall.com.
authors.forename: Monica
authors.initials: M
authors.lastname: Aparici
authors.affiliation: Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain. Electronic address: dolors.vilella@almirall.com.
authors.forename: Dolors
authors.initials: D
authors.lastname: Vilella
authors.affiliation: Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain. Electronic address: joan.alberti@almirall.com.
authors.forename: Joan
authors.initials: J
authors.lastname: Alberti
authors.affiliation: Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain. Electronic address: jorge.beleta@almirall.com.
authors.forename: Jorge
authors.initials: J
authors.lastname: Beleta
authors.affiliation: Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain. Electronic address: montse.miralpeix@almirall.es.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Miralpeix
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects; D001993:Bronchodilator Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D006024:Glycopyrrolate / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D006168:Guinea Pigs; D006207:Half-Life; D006801:Humans; D006868:Hydrolysis; D009241:Ipratropium / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D018727:Muscarinic Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012602:Scopolamine Derivatives / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D013045:Species Specificity; D013997:Time Factors; D000069447:Tiotropium Bromide; D014326:Tropanes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D001993:Bronchodilator Agents; D018727:Muscarinic Antagonists; D012602:Scopolamine Derivatives; D014326:Tropanes; D009241:Ipratropium; D000109:Acetylcholine; C542859:aclidinium bromide; D006024:Glycopyrrolate; D000069447:Tiotropium Bromide
keywords: Aclidinium; Aclidinium bromide (PubChem CID: 11519741); COPD; Glycopyrronium; Glycopyrronium bromide (PubChem CID: 11693); Ipratropium bromide (PubChem CID: 31098); Long-acting muscarinic antagonists; Muscarinic receptors; Preclinical; Tiotropium bromide (PubChem CID: 5487426)