Search

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.

The follicle-stimulating hormone (FSH) analog corifollitropin alfa (Org 36286) is a potent FSH receptor agonist with an extended plasma half-life due to the fusion of the carboxy-terminal peptide (CTP) of the human chorionic gonadotropin beta-subunit and the human FSH beta-subunit. The absorption, tissue distribution, metabolism and excretion of corifollitropin alfa were studied in rats following a single subcutaneous administration of [(125)I]corifollitropin alfa. The biological activity of [(125)I]corifollitropin alfa was confirmed by an in vitro FSH receptor transactivation assay. Radioactivity in blood, serum, tissues and excreta was determined by radiometry up to 168 h post dosage. A drug-specific distribution occurred mainly to ovaries and the renal system. The distribution was similar in albino and pigmented rats, ruling out effects of melanin binding on distribution. Metabolites were studied in urine and serum by SDS-PAGE. The maximum concentration of 12 h indicated a slow absorption and excretion. Radioactivity was mainly (86%) excreted via urine. 90% of the radioactivity in serum was identified as [(125)I]corifollitropin alfa, whereas only 7-15% of the radioactivity in urine was identified as [(125)I]corifollitropin alfa and its dissociation products, the alpha- and beta-subunits (including its CTP part). The remainder of the radioactivity in either matrix represented low-molecular-weight compounds resulting from catabolism and deiodination. In conclusion, the metabolic fate of corifollitropin alfa strongly resembles that of endogenous glycoprotein hormones, which predominantly consists of kidney clearance and the urinary excretion of the intact protein in parallel to kidney catabolism., (Copyright (c) 2010 S. Karger AG, Basel.)