Metabolic fate of the oral hypoglycaemic agent, midaglizole, in rats.
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)ethyl]pyridine O-glucuronide (M-XIV). These glucuronides accounted for 35.4% of the dose. 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.
Fujimaki
M
M
Drug Metabolism Research Center, Research Institute, Daiichi Seiyaku Co., Ltd, Tokyo, Japan.
Ishigaki
N
N
Hakusui
H
H
D000818:Animals; D001711:Biotransformation; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D007004:Hypoglycemic Agents / Q000378:metabolism*; D007093:Imidazoles / Q000378:metabolism* / Q000493:pharmacokinetics; D008297:Male; D013058:Mass Spectrometry; D011865:Radioisotope Dilution Technique; D051381:Rats; D011919:Rats, Inbred Strains
D002250:Carbon Radioisotopes; D007004:Hypoglycemic Agents; D007093:Imidazoles; C032368:midaglizole