Absorption, distribution, metabolism and excretion of the cholecystokinin-1 antagonist dexloxiglumide in the dog

• Published in: European journal of drug metabolism and pharmacokinetics 2004-01, Vol.29 (1), p.15-23
• Main Authors: WEBBER, C, STOKES, C. A, PERSIANI, S, MAKOVEC, F, MCBURNEY, A, KAPIL, R. P, JOHN, B. A, D'AMATO, M, CHASSEAUD, L. F
• Format: Article
• Language: English
• Subjects: Absorption; Animals; Biological and medical sciences; Digestive system; Dogs; Female; Male; Medical sciences; Metabolic Clearance Rate - drug effects; Metabolic Clearance Rate - physiology; Pentanoic Acids - administration & dosage; Pentanoic Acids - pharmacokinetics; Pharmacology. Drug treatments; Receptor, Cholecystokinin A - antagonists & inhibitors; Receptor, Cholecystokinin A - metabolism; Tissue Distribution - drug effects; Tissue Distribution - physiology
• ISSN: 0378-7966; 2107-0180
• DOI: 10.1007/BF03190569

Single oral doses of 14C-dexloxiglumide were rapidly and extensively absorbed in dogs and also eliminated rapidly with a short half-life. Following single intravenous doses, dexloxiglumide was characterised as a drug having a high clearance (30.7 and 27.0 ml/min/kg in males and females respectively), a low volume of distribution (Vss, 0.34 and 0.27 L/kg in males and females respectively) and a moderate systemic availability (about 33%). It was extensively bound to plasma proteins (89%). Dexloxiglumide is mainly cleared by the liver. Its renal clearance was minor. In only the kidney, liver and gastrointestinal tract, were concentrations of 14C generally greater than those in plasma. 14C concentrations generally peaked at 0.25h and declined rapidly during 24h being present only in a few tissues (such as the kidney, liver and gastrointestinal tract) at 24h. Single intravenous or oral doses were mainly excreted in the faeces (77-89%), mostly during 24h. Urine contained up to 7.5% dose. Mean recoveries during 7 days ranged between 93-97%. Biliary excretion of 14C was prominent (64% dose during 24h) in the disposition of 14C which was probably also subjected to some limited enterohepatic circulation. Unchanged dexloxiglumide was the major component in plasma. Urine and faeces contained several 14C-components amongst which unchanged dexloxiglumide was the most important (eg. about 55% dose in faeces). LC-MS/MS of urine and bile extracts showed that dexloxiglumide was metabolised mainly by O-demethylation and by conjugation with glucuronic acid.