K. Ohta et al., Retention mechanism of imidazoles in connective tissue. IV. Identificationof a nucleophilic imadazolone metabolite in rats, BIOL PHAR B, 21(12), 1998, pp. 1334-1337
Formation of a nucleophilic 4(5H)(or 5(4H))-imidazolone structure has been
postulated from in vitro studies to be one of the causative elements involv
ed in the retention of drugs with imidazole moiety in connective tissue. To
confirm this, we searched for the imidazolone-related metabolite in rats a
fter intravenous dosing of 2-methylimidazole (2MI; C-14-labeled and unlabel
ed form, 3 and 300 mu mol/kg body weight) as a model compound. The excreted
urine, the major route of elimination of the compound, was collected and a
nalyzed using the HPLC/MS system with a counterion effect for metabolite se
paration. 2-Methyl-4(5H)(or 5(4H))-imidazolone (2MIone) was identified as a
urinary metabolite by chromatographic and mass-spectral inspection with th
e corresponding authentic standard. Pretreatment of rats with either SKF-52
5A (50 mg/kg, i.p,) or cimetidine (200 mg/kg, i.p.) significantly increased
the excreted amount of 2MIone in urine and the irreversible binding of 2MI
equivalents in the aortic tissue, whereas both factors were reduced by pre
treatment with triethylenetetramine dihydrochloride (150 mg/kg/d for 5 d, s
.c,), These results support the aforementioned deduction, and also raise th
e possibility that a cytochrome P450-independent, copper-related metabolic
reaction might be involved in the imidazolone formation in vivo.