ADME properties of CHF6366, a novel bi-functional M3-Muscarinic receptor antagonist and ß-2 adrenoceptor agonist (MABA) radiolabeled at both functional moieties

Xenobiotica. 2023 Jun 27:1-59. doi: 10.1080/00498254.2023.2230490. Online ahead of print.ABSTRACTCHF6366, a dual action β2-receptor agonist and M3-muscarinic receptor antagonist developed for chronic obstructive pulmonary disease (COPD), was [14C]-radiolabeled on the two different functional moieties of the molecule (either aminobutanolic or carbamate) to characterize its ADME profile following intravenous (IV), intratracheal (IT) and oral (PO) administration.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.CHF6366 was observed fully hydrolyzed to alcohol (CHF6387) and carboxylic acid (CHF6361) in plasma and urine after IV and IT administration, and mainly unchanged in feces 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.The major metabolic routes of the alcoholic moiety (CHF6387) included isomerization (Ma7), conjugation with glucuronic acid and dehydrogenation, while the carboxylic acid moiety (CHF6361) was mainly metabolized through oxidation, glucuronide conjugation and, in both pathways, combinations of those metabolic reactions.No major differences arose also from in vitro metabolism profiles investig...
Source: Xenobiotica - Category: Research Authors: Source Type: research