Biotransformation of linogliride, a hypoglycemic agent in laboratory animals and humans.
Following oral administration of linogliride, a hypoglycemic agent, to rat (50 mg kg-1), dog (30 mg kg-1), and man (100 mg per subject), plasma, urine, and fecal extract sample pools were obtained. Nine metabolites plus unchanged linogliride were isolated and identified. The number of metabolites identified were: rat (5), dog (9), and man (1). In each species, more than 78% of the administered dose was recovered in the urine pools. Identified metabolites were estimated to account for > 82% of the total amounts of drug-related sample in urine pools and > 50% in plasma and fecal extract pools. Formation of linogliride metabolites in the three species can be described by four proposed pathways: pyrrolidine hydroxylation, aromatic hydroxylation, morpholine hydroxylation, and imino-bond cleavage. Comparison of the proposed metabolic pathways among species reveals a similarity between rat and dog. In these two species, pyrrolidine hydroxylation was quantitatively the most important pathway, with 5-hydroxylinogliride and dominant hypoglycemic active metabolite in all sample pools. Further oxidation of 5-hydroxylinogliride resulted in the formation of five minor metabolites. The other three pathways appeared to be quantitatively unimportant. Metabolism of linogliride in man occurred to a very limited extent. More than 90% of the total linogliride-related material in plasma was the unchanged drug. Greater than 76% of the administered dose was excreted unchanged in the urine. Only 5-hydroxylinogliride was identified in minor amounts in human samples.
Wu
W N
WN
Department of Drug Metabolism, R.W. Johnson Pharmaceutical Research Institute, Spring House, PA 19477, USA.
Mutter
M S
MS
D000818:Animals; D001711:Biotransformation; D002853:Chromatography, Liquid; D002855:Chromatography, Thin Layer; D004285:Dogs; D005243:Feces / Q000737:chemistry; D006801:Humans; D007004:Hypoglycemic Agents / Q000302:isolation & purification / Q000378:metabolism / Q000493:pharmacokinetics*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D011759:Pyrrolidines / Q000302:isolation & purification / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D013055:Spectrophotometry, Infrared
D007004:Hypoglycemic Agents; D011759:Pyrrolidines; C044425:linogliride