title: Metabolism and excretion of asenapine in healthy male subjects.
abstract: The metabolism and excretion of asenapine [(3aRS,12bRS)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]-oxepino [4,5-c]pyrrole (2Z)-2-butenedioate (1:1)] were studied after sublingual administration of [(14)C]-asenapine to healthy male volunteers. Mean total excretion on the basis of the percent recovery of the total radioactive dose was ∼90%, with ∼50% appearing in urine and ∼40% excreted in feces; asenapine itself was detected only in feces. Metabolic profiles were determined in plasma, urine, and feces using high-performance liquid chromatography with radioactivity detection. Approximately 50% of drug-related material in human plasma was identified or quantified. The remaining circulating radioactivity corresponded to at least 15 very polar, minor peaks (mostly phase II products). Overall, >70% of circulating radioactivity was associated with conjugated metabolites. Major metabolic routes were direct glucuronidation and N-demethylation. The principal circulating metabolite was asenapine N(+)-glucuronide; other circulating metabolites were N-desmethylasenapine-N-carbamoyl-glucuronide, N-desmethylasenapine, and asenapine 11-O-sulfate. In addition to the parent compound, asenapine, the principal excretory metabolite was asenapine N(+)-glucuronide. Other excretory metabolites were N-desmethylasenapine-N-carbamoylglucuronide, 11-hydroxyasenapine followed by conjugation, 10,11-dihydroxy-N-desmethylasenapine, 10,11-dihydroxyasenapine followed by conjugation (several combinations of these routes were found) and N-formylasenapine in combination with several hydroxylations, and most probably asenapine N-oxide in combination with 10,11-hydroxylations followed by conjugations. In conclusion, asenapine was extensively and rapidly metabolized, resulting in several regio-isomeric hydroxylated and conjugated metabolites.
authors.affiliation: Department of Toxicology, Early Stage Development and Process Chemistry, Merck Sharp and Dohme, Oss, The Netherlands.
authors.forename: S F M
authors.initials: SF
authors.lastname: van de Wetering-Krebbers
authors.forename: P L
authors.initials: PL
authors.lastname: Jacobs
authors.forename: G J
authors.initials: GJ
authors.lastname: Kemperman
authors.forename: E
authors.initials: E
authors.lastname: Spaans
authors.forename: P A M
authors.initials: PA
authors.lastname: Peeters
authors.forename: L P C
authors.initials: LP
authors.lastname: Delbressine
authors.forename: M L P S
authors.initials: ML
authors.lastname: van Iersel
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D019540:Area Under Curve; D003986:Dibenzocycloheptenes; D020719:Glucuronides / Q000032:analysis* / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D006801:Humans; D006900:Hydroxylation; D008297:Male; D008875:Middle Aged; D011869:Radioligand Assay; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D003986:Dibenzocycloheptenes; D020719:Glucuronides; D006576:Heterocyclic Compounds, 4 or More Rings; C522667:asenapine