Metabolism and disposition of 2-methoxy-4-nitroaniline in male and female Harlan Sprague Dawley rats and B6C3F₁/N mice

Abstract

1. The disposition of 2-Methoxy-4-nitroaniline (MNA) was investigated in male and female Harlan Sprague Dawley rats and B6C3F₁/N mice following oral, intravenous, and dermal exposure to [¹⁴C]MNA at 2, 15, or 150 mg/kg. Clearance of MNA was investigated in male and female rat, mouse, and human hepatocytes.

2. MNA was cleared slowly in hepatocytes from rat (t_1/2 = 152–424 min) and human (t_1/2 = 118–403 min) but faster in mouse (t_1/2= 70–106 min).

3. MNA was well-absorbed in rats and mice following oral administration and eliminated chiefly in urine (rats, 75–79%; mice, 55–68%) 72 h post dosing. Less than 1% of the radioactivity remained in tissues at 72 h. MNA was poorly absorbed following dermal application in rats (5.5%) and mice (10%) over 24 h.

4. The major pathway of metabolism of MNA was via hydroxylation of the phenyl ring to form 6-hydroxy MNA; major metabolites detected were sulfate and glucuronide conjugates of 6-hydroxy MNA.

5. Following oral administration, the percent of total radioactivity bound in tissues bound was highest in liver (43%) and red blood cells (30%), whereas the radioactivity bound to DNA was highest in cecum (160 pmol/mg DNA).

Keywords::

• 2-Methoxy-4-nitroaniline
• DNA binding
• hepatocytes
• dermal absorption
• oral absorption

Acknowledgements

The authors are grateful to Drs Michael J Sanders and Helen Cunny for their review of this manuscript, and Ms. Kathy Ancheta for her assistance in preparation of the manuscript.This work was performed for the National Toxicology Program, National Institute of EnvironmentalHealth Sciences, National Institutes of Health, U.S. Department of Health and Human Services, under contract No. N01-ES-75563 (HHSN29120077563). 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.

Declaration of interest

The authors report no conflicts of interest.