Metabolism and Excretion of Asenapine in Healthy Male Subjects

• Published in: Drug metabolism and disposition Vol. 39; no. 4; pp. 580 - 590
• Main Authors: van de Wetering-Krebbers, SFM, Jacobs, PL, Kemperman, GJ, Spaans, E, Peeters, PAM, Delbressine, LPC, van Iersel, MLPS
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.04.2011; American Society for Pharmacology and Experimental Therapeutics
• Subjects: Adult; Antipsychotic Agents - blood; Antipsychotic Agents - chemistry; Antipsychotic Agents - metabolism; Antipsychotic Agents - urine; Area Under Curve; Biological and medical sciences; Dibenzocycloheptenes; General pharmacology; Glucuronides - analysis; Glucuronides - metabolism; Heterocyclic Compounds, 4 or More Rings - blood; Heterocyclic Compounds, 4 or More Rings - chemistry; Heterocyclic Compounds, 4 or More Rings - metabolism; Heterocyclic Compounds, 4 or More Rings - urine; Humans; Hydroxylation; Male; Medical sciences; Middle Aged; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Radioligand Assay; Young Adult; MIM; 2D; a.o; MS; LC; SK&F 86466; SPE; TOCSY; MS/MS; LSC; HPLC; ES; Human; Biological fluid; Excretion; Healthy subject; CNS stimulant; Psychotropic; Exploration; Asenapine; Feces; Pharmacokinetics; Metabolism; Quantitative analysis
• ISSN: 0090-9556; 1521-009X; 1521-009X
• DOI: 10.1124/dmd.110.036715

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.