The metabolism and excretion of asenapine (3aRS,12bRS)-5- chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo2,3:6,7-oxepino 4,5-cpyrrole (2Z)-2-butenedioate (1:1) were studied after sublingual administration of 14C-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 detec- tion. 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-hydroxyasenap- ine followed by conjugation, 10,11-dihydroxy-N-desmethylasenapine, 10,11-dihydroxyasenapine followed by conjugation (several combina- tions of these routes were found) and N-formylasenapine in combi- nation 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.
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