Absorption, Metabolism, and Excretion of [¹⁴C]Imidafenacin, a New Compound for Treatment of Overactive Bladder, After Oral Administration to Healthy Male Subjects

Abstract

ABSTRACT:The absorption, metabolism, and excretion of imidafenacin [KRP-197/ONO-8025, 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanamide], a new antimuscarinic drug developed for treatment of overactive bladder, were assessed in six healthy male subjects after a single oral administration of 0.25 mg of [ 14 C]imidafenacin (approximately 46 Ci). The highest radioactivity in the plasma was observed at 1.5 h after administration. The apparent terminal elimination half-life of the total radioactivity was 72 h. Approximately 65.6 and 29.4% of the administered radioactivity were recovered in the urine and feces, respectively, within 192 h after administration. The metabolite profiling by high-performance liquid chromatography-radiodetector and liquid chromatography/tandem mass spectrometry demonstrated that the main component of radioactivity was unchanged imidafenacin in the 2-h plasma. The N-glucuronide conjugate (M-9) was found as the major metabolite and the oxidized form of the 2-methylimidazole moiety (M-2) and the ringcleavage form (M-4) were detected as the minor metabolites in the 2-h plasma, but M-4 was found to be the main component in the 12-h plasma. Unchanged imidafenacin, M-9, M-2, and other oxidized metabolites were excreted in the urine, but the unchanged imidafenacin and M-9 were not found in the feces. Two unique metabolites were found in the urine and feces, which were identified as the interchangeable cis-and trans-isomers of 4,5-dihydrodiol forms of the 2-methylimidazole moiety. These findings indicate that imidafenacin is rapidly and well absorbed (at least 65% of dose recovered in urine) after oral administration, circulates in human plasma as the unchanged form, its glucuronide, and other metabolites, and is then excreted in urine and feces as the oxidized metabolites of 2-methylimidazole moiety.Imidafenacin [KRP-197/ONO-8025, 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanamide] (Fig. 1) is a newly synthesized antimuscarinic drug developed for treatment of overactive bladder. Acetylcholine is well known for playing a major role in contracting the bladder through activation of muscarinic receptors (Somogyi and de Groat, 1992;Wang et al., 1995;Braverman et al., 1998). Compounds with high affinity for the muscarinic acetylcholine receptor, including propiverine, tolterodine, oxybutynin, darifenacin, and solifenacin, have been used in management of overactive bladder (Chapple et al., 2002;Andersson and Yoshida, 2003;Andersson, 2004;Robinson and Cardozo, 2005). Imidafenacin showed high in vitro affinity for muscarinic receptor subtypes M 1 and M 3 in the functional assay using isolated animal tissues and in the binding assay using recombinant human receptors (Miyachi et al., 1999;Kobayashi et al., 2007a). In addition, imidafenacin inhibited carbachol-induced contraction of isolated guinea pig and human bladder mediated by the M 3 receptor and acetylcholine release from isolated rat and human bladder mediated by the prejunctional M 1 receptor (Murakami et al., 2003;Kobayashi et al., 2007a). A car...

Application of Modern Drug Metabolism Structure Determination Tools and Assays to the In Vitro Metabolism of Imiloxan

“…Rush et al called this metabolite RM8 and assigned a 4-hydroxy,5-ketoimidazoline structure. We prefer an M2 structure comparable to the ring opened metabolite of imidafenacin [13]. Our structure is consistent with the observed 3 deuterium exchangeable hydrogens.…”

“…In MS/MS it had a unique loss of 75 Da (C 2 H 5 NO 2 ) and small a and b ions displaced 34 Da each. This spectral data is consistent with the dihydrodiol structure drawn in analogy to M12 in the metabolism of imidafenacin [13]. The relative retention time was also comparable to the corresponding imidafenacin metabolite.…”

“…In MS/MS they show much less abundant a and b ions displaced 32 Da, instead these isomers fragment predominantly between the benzodioxane piece and the methylene bridge to yield m/z 135 and m/z 143. These metabolites were called RM5 and RM6 by Rush et al They show the long retention time seen for the comparable metabolites of imidafenacin [13]. The presence of a saturated imidazole C2-3 bond was supported by the NMR data [5] and by the presence of two diastereomers.…”

Imidafenacin for the treatment of overactive bladder

“…Plasma concentration is dose dependent and increases linearly, with an elimination halflife of about 3 h. The compound is eliminated primarily by hepatic metabolism: the major enzymes responsible of its metabolism are CYP3A4 and UGT1A4; oxidative metabolism of imidafenacin is reduced by concomitant administration of CYP3A4 inhibitors [26]. The oxidized form of the compound (M-2) and the N-glicuronide conjugate (M-9) are the major metabolites [27]. CYP3A4 seems to have a role in metabolizing imidafenacin in M-2 and UGT1A4 seems to play a role in metabolizing imidafenacin in M-9.…”

Identification of Novel Metabolites of Rosiglitazone in Freshly Isolated Human, Rat, and Monkey Hepatocytes by Liquid Chromatography/Tandem Mass Spectrometry

“…N-Glucuronides of heterocyclic compounds have been reported, e.g., a glucuronide on a nitrogen of a benzoxazin-2-one moiety of efavirenz 27) and a glucuronide on a nitrogen of an imidazole moiety of imidafenacin. 28) However, N-glucuronide of a TZD ring is first reported in this study.…”