Pharmacokinetics, metabolism, and excretion of nefopam, a dual reuptake inhibitor in healthy male volunteers

Abstract

1. The disposition of nefopam, a serotonin–norepinephrine reuptake inhibitor, was characterized in eight healthy male volunteers following a single oral dose of 75 mg [¹⁴C]-nefopam (100 μCi). Blood, urine, and feces were sampled for 168 h post-dose.

2. Mean (± SD) maximum blood and plasma radioactivity concentrations were 359 ± 34.2 and 638 ± 64.7 ngEq free base/g, respectively, at 2 h post-dose. Recovery of radioactive dose was complete (mean 92.6%); a mean of 79.3% and 13.4% of the dose was recovered in urine and feces, respectively.

3. Three main radioactive peaks were observed in plasma (metabolites M2 A-D, M61, and M63). Intact [¹⁴C]-nefopam was less than 5% of the total radioactivity in plasma. In urine, the major metabolites were M63, M2 A-D, and M51 which accounted for 22.9%, 9.8%, and 8.1% of the dose, respectively. An unknown entity, M55, was the major metabolite in feces (4.6% of dose). Excretion of unchanged [¹⁴C]-nefopam was minimal.

• Human disposition
• mass balance
• metabolite profiling and identification
• radiolabeled nefopam

Acknowledgements

The authors thank Drs. Gopal Damodara and Jason Smulik at Ricerca Biosciences for synthesis of radiolabeled nefopam; Xiaohong Liu, James Pombier, Sara Wills, Lori Joas, and Mike Potchoiba at Covance Laboratories for help with conduct and analysis of the study; Eric Solon at QPS for estimating human radiation dosimetry; and Weiru Hong at Impax for assistance with the clinical conduct of the study.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

A. Mittur and Nishit B. Modi are employees of Impax Laboratories, Inc. and hold Impax stock.