Abstract

To elucidate the retention mechanism of drugs with imidazole moiety in the connective tissue, the retention form and site of [2-14C]imidazole and 2-methyl[2-14C]imidazole were studied after intravenous administration to rats (3 micromol/kg body weight). The aorta, which is representative of the connective tissue, retained considerable radioactivity after dosing for both the imidazoles. It was observed that most of the aortic radioactivity came from the irreversibly bound fraction with elastin and that this was in close agreement with the microautoradiographic observation that showed that the retention of radioactivity occurred near the elastic fiber in the aorta. Pretreatment of rats with SKF525-A significantly increased the irreversible binding of radioactivity from the imidazoles in aorta, whereas neither phenobarbital nor 3-methylcholanthrene increased the binding. Regarding the urinary metabolite profile, the excretion of intact form significantly increased by SKF525-A pretreatment for imidazole, and an increasing tendency was also observed for 2-methylimidazole. However, no in vitro irreversible binding of imidazoles to aortic tissue was observed after incubating at physiological pH and temperature. These findings indicate that the retention of drugs with imidazole moiety in the connective tissue is largely attributable to irreversible binding between the imidazole moiety and elastin, and that the binding may be mediated through cytochrome P450-independent biotransformation.