Disposition and metabolism of N,N-dimethylacetoacetamide in male F344 and Wistar-Han rats and female B6C3F1 mice

Abstract

1. N,N-dimethylacetoacetamide (DMAAm) is a β-dicarbonyl compound used as an industrial intermediate. This study investigated the disposition and metabolism of [¹⁴C]DMAAm in male rats and female mice.

2. A single oral dose of [¹⁴C]DMAAm (target dose of 10 or 130 mg/kg) was administered to male F344 and Wistar-Han rats. [¹⁴C]DMAAm was almost completely absorbed and excreted in urine, with ca. 80−90% of the dose recovered within 24 h for both rat strains. Fecal excretion and CO₂ exhalation were minimal (1 and 2%, respectively). Less than 3% of the dose remained in tissues at 24 h. There was no apparent dose- or strain-related difference in the disposition of [¹⁴C]DMAAm in rats.

3. In female B6C3F1 mice administered 8 mg/kg [¹⁴C]DMAAm, 80% of the administered radioactivity was recovered in urine and cage rinse in 24 h.

4. Urinary metabolites were isolated and characterized by liquid chromatography /mass spectrometry following oral administration of 435 mg/kg [¹⁴C]DMAAm in male F344 rats. Metabolism occurred via reduction of the 3-keto group and oxidation of the N-methyl groups, to give N,N-dimethyl-3-hydroxybutanamide, N-methyl-N-hydroxymethyl-3-hydroxybutanamide, and N-hydroxymethyl-3-hydroxybutanamide, and N-demethylation to give N-monomethylacetoacetamide (MMAAm).

Keywords::

• Dimethylacetoacetamide
• metabolism
• disposition

Acknowledgments

The authors are grateful to Drs. J. Michael Sanders and Helen Cunny for their review of this manuscript. This work was performed for the National Toxicology program, National Institute of Environmental Health Sciences, National Institutes of Health, U.S. Department of Health and Human Services, under Contract No. N01-ES-75563 (HHSN29120077563).

Declaration of interest

The authors state no conflict of interst. This article may be the work product of an employee or group of employees of the National Institute of Environmental Health Sciences (NIEHS), National Institute of Health (NIH); however, the statements, opinions, or conclusions contained therein do not necessarily represent the statements, opinions, or conclusions of NIEHS, NIH, or the United States Government.