Disposition of Orally and Intravenously Administered Methyltetrahydrofuran in Rats and Mice

Abstract

The disposition of [¹⁴C]methyltetrahydrofuran (¹⁴C-MTHF) in rats and mice was determined by following changes in the radioactivity in tissue and excreta with time after dosing. MTHF administered orally (1, 10, or 100 mg/kg) or intravenously (1 mg/kg) to either rats or mice was rapidly metabolized and excreted with <8% (mice) or 8–22% (rats) of the dose remaining in the body after 24 h (1 and 10 mg/kg doses) or 72 h (100 mg/kg dose). Based on recovery of radioactivity in excreta (other than feces) and tissues (other than the gastrointestinal [GI] tract), absorption of orally administered MTHF was essentially complete (93–100%). There were no overt signs of toxicity observed at any dose studied. The major route of excretion in mice was in urine followed by exhaled CO₂. In rats the major route of excretion was exhaled CO₂ followed by urinary excretion. The excretion of exhaled volatile organic compounds (VOC) was dose-dependent in both species; at lower doses exhaled VOC represented 1–5% of dose, but at the highest dose (100 mg/kg) this proportion rose to 14% (mice) and 27% (rats). Analysis of the VOCs exhaled at the high dose indicated that the increase was due to exhalation of the parent compound, ¹⁴C-MTHF. Analysis of urine showed three highly polar peaks in the mouse urine and two polar peaks in the rat urine. Because the ¹⁴C label in MTHF was in the methyl group, the polar metabolites were considered likely due to the one-carbon unit getting into the metabolic pool and labeling intermediate dietary metabolites.

The authors acknowledge the support of the staff of the Lovelace Respiratory Research Institute. In conducting research using animals, the investigator(s) adhered to the Guide for the Care and Use of Laboratory Animals, prepared by the Committee on Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council (NIH publication 86-23, revised 1985). The facilities used for this research were fully accredited by the American Association for Accreditation of Laboratory Animal Care. The project has been funded in whole or in part with federal funds from the National Institute of Environmental Health Sciences, National Institutes of Health, under contract N01-ES-25483.