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Abstract
1. The metabolic fate of midaglizole, 2-[2-(4,5-dihydro-1H-imidazole-2-yl)-1-phenylethyl]pyridine dihydrochloride sesquihydrate, was studied in rats after a single oral dose of 10 mg/kg.
2. After oral administration of 14C-midaglizole to rats, 63% of the dose was excreted in the urine and 41% in the faeces within 72 h. The major radioactive compound in the urine was unchanged midaglizole and accounted for 38.1% of the dose. In the faeces, two major radioactive compounds, M-VII and unchanged midaglizole, were present. These accounted for 17.2 and 14.1% of the dose, respectively. M-VII is a new metabolite, identified as 2-[2-(4,5-dihydro-1H-imidazole-2-yl)-1-(4-hydroxyphenyl)ethyl]pyridine by n.m.r. and mass spectrometry.
3. The biliary excretion of the radioactivity after oral administration of 14C-midaglizole to bile-duct cannulated rats amounted to 53% of the dose. Of the total amount of radioactivity excreted in the bile, 48% was calculated to be subject to enterohepatic recycling.
4. Four biliary metabolites were new metabolites and were identified by n.m.r., mass spectrometry and enzymic hydrolysis. These compounds are 2-[2-(4,5-dihydro-1H-imidazole-2-yl)-1-(4-hydroxyphenyl)-ethyl]pyridine O-glucuronide (M-XI), 2-[2-(4-hydroxyphenyl)-2-(2-pyridyl)]ethyl-2-imidazole O-glucuronide (M-XII), 3-(4-hydroxyphenyl)-3-(2-pyridyl)propioimidamide O-glucuronide (M-XIII) and 2-[2-(4,5-dihydro-1H-imidazole-2-yl)-1-(4-hydroxy-3-methoxyphenyl)
5. Midaglizole was metabolized in rats mainly via phenyl ring para-hydroxylation followed by glucuronidation, with or without the biotransformation of the imidazoline ring moiety.