Metabolism and Excretion of Asenapine in Healthy Male Subjects

Abstract

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 ϳ90%, with ϳ50% appearing in urine and ϳ40% 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, Ndesmethylasenapine, and asenapine 11-O-sulfate. In addition to the parent compound, asenapine, the principal excretory metabolite was asenapine N ؉ -glucuronide. Other excretory metabolites were Ndesmethylasenapine-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.

Glucuronidation of the second-generation antipsychotic clozapine and its active metabolite N-desmethylclozapine. Potential importance of the UGT1A1 A(TA)7TAA and UGT1A4 L48V polymorphisms

“…The uridine diphosphate (UDP)-glucuronosyltransferases (UGTs) are one group of Phase II enzymes that mediate greater than one-third of Phase II drug metabolism [18] and influence the plasma levels and clearance of a given compound [19]. UGTs are important to the biotransformation and clearance of several second-generation antipsychotics as evidenced by plasma and urine metabolites in humans [20–24]. CLZ undergoes extensive biotransformation, with 97% of the administered dose being metabolized [15].…”

Quantification of asenapine and three metabolites in human plasma using liquid chromatography–tandem mass spectrometry with automated solid‐phase extraction: application to a phase I clinical trial with asenapine in healthy male subjects

“…The proposed metabolism of ASE and the excretion profiles were recently published (Van de Wetering‐Krebbers et al , ). The proposed biotransformation scheme for ASE based on the structure proposals of the metabolites characterized is depicted in Fig.…”

Stability-Indicating Liquid Chromatographic Method for the Quantification of the New Antipsychotic Agent Asenapine in Bulk and in Pharmaceutical Formulation

“…In short-term trials, ASP has demonstrated superiority over placebo in the treatment of schizophrenia [4, 5] and acute manic episodes associated with bipolar I disorder [6, 8]. The proposed metabolism of ASP and the excretion profiles were recently published [9]. …”