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 [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 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.
Footnotes
This work was supported by Schering-Plough Corporation; and Pfizer Inc. Editorial support was provided by Complete Healthcare Communications, Inc., and funded by Merck.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.036715.
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ABBREVIATIONS:
- LSC
- liquid scintillation counting
- HPLC
- high-performance liquid chromatography
- SPE
- solid-phase extraction
- LC
- liquid chromatography
- MS/MS
- tandem mass spectrometry
- MS
- mass spectrometry
- ES
- electrospray
- a.o.
- among others
- MIM
- monoisotopic molecular mass
- TOCSY
- total correlation spectroscopy
- 2D
- two-dimensional
- SK&F 86466
- 6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine.
- Received October 12, 2010.
- Accepted December 22, 2010.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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