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Drug Metab Dispos. 2010 Jul;38(7):1202-10. doi: 10.1124/dmd.109.031724. Epub 2010 Mar 23.

Identification of the human enzymes responsible for the enzymatic hydrolysis of aclidinium bromide.

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1
Department of Pharmacokinetics and Drug Metabolism, Almirall, S.A., 08980 Sant Feliu de Llobregat, Barcelona, Spain. joan.alberti@almirall.com

Abstract

Aclidinium bromide [LAS34273, 3R-(2-hydroxy-2,2-dithiophen-2-yl-acetoxy)-1-(3-phenoxy-propyl)1-azonia bicycle-[2.2.2]-octane bromide], a novel, long-acting, inhaled muscarinic antagonist for the treatment of chronic obstructive pulmonary disease, has shown rapid hydrolysis in human and animal plasma. This process occurred both nonenzymatically (k(h), 0.0075 min(-1)) and enzymatically. The purpose of the current study was to investigate the in vitro enzymatic hydrolysis of aclidinium in humans. Human butyrylcholinesterase was identified as the most important esterase responsible for the enzymatic hydrolysis of aclidinium from inhibition studies in human plasma with selective paraoxonase, arylesterase, carboxylesterase, acetylcholinesterase, and butyrylcholinesterase chemical inhibitors, as well as from incubations with pure human cholinesterases. Furthermore, neither human cytochrome P450 nor human serum albumin participated in the enzymatic ester cleavage of aclidinium. Butyrylcholinesterase activity in the human lung was lower than that observed in human plasma. Aclidinium was shown to inhibit competitively both human butyrylcholinesterase (K(i), 2.7 microM) and acetylcholinesterase (6.3 microM) but did not have any effect on the activity of other human esterases, as well as its hydrolysis metabolites. These results suggest that the potential for clinical interactions involving human cholinesterases is remote at clinically relevant plasma, which are less than 1 nM.

PMID:
20332199
DOI:
10.1124/dmd.109.031724
[Indexed for MEDLINE]
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