Received for publication April 3, 2007.
Revised May 25, 2007.
Accepted for publication June 12, 2007.

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

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 following a single oral administration of 0.25 mg [¹⁴C]imidafenacin (ca. 46 µCi). 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 HPLC radiodetector and LC/MS/MS demonstrated the main component of radioactivity was unchanged imidafenacin in the 2 h plasma. N-glucuronide conjugate (M-9) was found as the major metabolite, and the oxidized form of 2-methyl-imidazole moiety (M-2) and the ring-cleavage 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-dihydro-diol forms of 2-methyl-imidazole moiety. These findings indicate that imidafenacin is rapidly and well absorbed (at least 65% of dose recovered in urine) following oral administration and circulates in human plasma as the unchanged form, its glucuronide and other metabolites, then excreted in urine and feces as the oxidized metabolites of 2-methyl-imidazole moiety.

Key words: analytical chemistry, CYP2D, metabolite identification, pharmacokinetics

This article has been cited by other articles:

				T. Ohno, K. Nakayama, S. Nakade, J. Kitagawa, S. Ueda, H. Miyabe, Y. Miyata, and A. Ohnishi Effect of Itraconazole on the Pharmacokinetics of Imidafenacin in Healthy Subjects J. Clin. Pharmacol., March 1, 2008; 48(3): 330 - 334. [Abstract] [Full Text] [PDF]