Toxicokinetics of 2-methylimidazole in male and female F344 rats.
The toxicokinetics of 2-methylimidazole (2-MI) were studied in male and female Fischer 344 rats after a single iv dose of 10 mg/kg or gavage dose of 25, 50, or 100 mg/kg. The 2-MI was formulated in 0.05 M phosphate-buffered saline (pH 7.4). The iv profiles could be best described by a two-compartment model with first-order elimination. The terminal elimination half-life, volume of distribution at steady state, and clearance values were 0.78 and 0.85 h(-1), 1.5 and 1.9 L, and 4.97 and 12.0 L/h/kg for males and females, respectively. After a gavage dose, the plasma concentration time profiles could be best described by a one-compartment model, no lag phase, and first-order absorption and elimination. The peak 2-MI plasma concentrations increased proportionately with dose and were reached within 35 to 50 min (T(max)) for all groups. The estimated half-life value for 2-MI was about 1 h for the iv group and the male 25-, 50-, or 100-mg/kg groups and female 25-mg/kg groups. Clearance increased for the male 100- and female 50- and 100- mg/kg groups. For a given dose group, clearance was also two to three times greater for female rats when compared to male rats. Absolute bioavailability for 2-MI was estimated to approach 97%. The results of this study indicated that 2-MI was (1) rapidly and completely absorbed, (2) quickly eliminated, (3) cleared differently for females than for males, (4) affected somewhat by dose for females, and (5) unlikely to undergo tissue accumulation following repeated exposure.
Johnson
Jerry D
JD
Battelle Memorial Institute, Columbus, Ohio 43201, USA. johnsojd@battelle.org
Reichelderfer
Diana
D
Zutshi
Anup
A
Graves
Steven
S
Walters
Denise
D
Smith
Cynthia
C
D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D006207:Half-Life; D007093:Imidazoles / Q000008:administration & dosage / Q000633:toxicity*; D007275:Injections, Intravenous; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D012737:Sex Factors; D014018:Tissue Distribution
D004785:Environmental Pollutants; D007093:Imidazoles; C032655:2-methylimidazole