ADME properties of CHF6366, a novel bi-functional M3 muscarinic receptor antagonist and ß₂ adrenoceptor agonist (MABA) radiolabelled at both functional moieties

Abstract

1. CHF6366, a dual action β₂-receptor agonist and M3-muscarinic receptor antagonist developed for chronic obstructive pulmonary disease (COPD) was [¹⁴C]-radiolabelled on the two different functional moieties of the molecule (either aminobutanolic or carbamate) to characterise its ADME profile following intravenous (IV), intratracheal (IT) and oral (PO) administration.

2. A very low oral bioavailability and a good balance between absorption and lung retention after IT administration were observed, together with a rapid distribution throughout the body and a complete metabolic transformation of the parent drug without relevant gender difference.

3. CHF6366 was observed fully hydrolysed to alcohol (CHF6387) and carboxylic acid (CHF6361) in plasma and urine after IV and IT administration, and mainly unchanged in faeces only after oral administration. An important number of metabolites containing aminobutanolic moiety was excreted via urine, whereas carbamate-containing derivatives were excreted mainly by bile.

4. The major metabolic routes of the alcoholic moiety (CHF6387) included isomerisation (Ma7), conjugation with glucuronic acid and dehydrogenation, while the carboxylic acid moiety (CHF6361) was mainly metabolised through oxidation, glucuronide conjugation and, in both pathways, combinations of those metabolic reactions.

5. No major differences arose also from in vitro metabolism profiles investigated using liver microsomes and hepatocytes of different species.

Keywords:

• ADME
• 14C-labelled
• in vitro metabolism
• in vivo metabolism
• COPD
• MABA

Acknowledgments

We thank M. Anelli, L. Biagini, E. Cozzi and S. Meli for the experimental in vivo phase, F. Fiorentini, C. Pellizzoni and R. Spinelli for PK analysis.

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The authors report no declarations of interest.

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Funding

The author(s) reported there is no funding associated with the work featured in this article.