文章基本信息

标题：Retention Mechanism of Imidazoles in Connective Tissue. IV. Identification of a Nucleophilic imidazolone Metabolite in Rats
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作者：Katsuji OHTA ; Yoshiki FUKASAWA ; Jun-ichi YAMAGUCHI 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：1998
卷号：21
期号：12
页码：1334-1337
DOI：10.1248/bpb.21.1334
出版社：The Pharmaceutical Society of Japan
摘要：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 involved in the retention of drugs with imidazole moiety in connective tissue.To confirm this, we searched for the imidazolone-related metabolite in rats after intravenous dosing of 2-methylimidazole (2MI; ¹⁴C-labeled and unlabeled form, 3 and 300 μmol/kg body weight) as a model compound.The excreted urine, the major route of elimination of the compound, was collected and analyzed using the HPLC/MS system with a counterion effect for metabolite separation. 2-Methyl-4(5H)(or 5(4H))-imidazolone (2MIone) was identified as a urinary metabolite by chromatographic and mass-spectral inspection with the corresponding authentic standard. Pretreatment of rats with either SKF-525A (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 pretreatment with triethylenetetramine dihydrochloride (150 mg/kg/d for 5 d, s.c.). These results support the aforementioned deduction, and also raise the possibility that a cytochrome P450-independent, copper-related metabolic reaction might be involved in the imidazolone formation in vivo.
关键词：imidazolone;covalent binding;connective tissue;nucleophilic metabolite;rat