Dimethylformamide Pharmacokinetics Following Inhalation Exposure in Monkeys

ABSTRACT

Male and female cynomolgus monkeys received whole-body inhalation exposures to dimethylformamide (DMF) at concentrations of 30, 100, and 500 ppm for 6 hours a day, 5 days a week over a 13–week period. serial blood samples were drawn at the conclusion of the first day of exposure and following 15, 29, 57, and 85 days of testing. Area under the plasma concentration curve (AUC) values were determined for DMF and “NMF” [N-methylformamide (NMF) plus N-(hydroxymethyl) -N-methylformamide (DMF-OH)]. Urine samples were also collected and assayed for DMF, NMF and DMF-OH.

The systemic exposure to DMF increased disproportionately as the airborne DMF concentrations increased. DMF AUC values increased 19- to 37-fold in male and 35- to 54-fold in female monkeys as the inhalation concentrations increased 5–fold (100 to 500 ppm). These data are consistent with saturation of DMF metabolism as inhaled DMF concentrations increased from 100 to 500 ppm. AUC values, peak plasma concentrations, and plasma half-lives were essentially unaltered over the duration of the study within each exposure concentration tested. Estimated plasma half-lives ranged from 1 to 2 hours and 4 to 15 hours for DMF and “NMF” respectively. DMF was rapidly converted to “NMF” following 30 ppm exposures, with “NMF” plasma concentrations higher than DMF plasma concentrations at the 0.5 hour timepoint. In plasma samples simultaneously assayed for DMF-OH and NMF, the concentration of DMF-OH exceeded, was equal to, or was less than NMF concentrations depending upon the plasma sample. DMF-OH was always the main urinary metabolite (56 to 95 percent) regardless of exposure level or time on study.