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

Single oral doses of C-14-dexloxigiumide were rapidly and extensively absorbed in rats, and eliminated more slowly by females than by mates. The respective half-lives were about 4.9 and 2.1h. Following single intravenous doses, dexioxiglumide was characterised as a drug having a low clearance (6.01 and about 1.96 ml/min/kg in males and females respectively), a moderate volume of distribution (Vss, 0.98 and about 1.1 L/kg in males and females respectively) and a high systemic availability. It was extensively bound to plasma proteins (97%). Dexloxiglumide is mainly cleared by the liver. Its renal clearance was minor. In only the liver and gastrointestinal tract, were concentrations of C-14 generally greater than those in plasma. Peak C-14 concentrations generally occurred at 1-2h in males and at 2-4h in females. Tissue C-14 concentrations then declined by severalfold during 24h although still present in most tissues at 24h but only in a few tissues (such as the liver and gastrointestinal tract) at 168h. Decline of C-14 Was less rapid in the tissues of females than in those of males. Single intravenous or oral doses were mainly excreted in the faeces (87-92%), mostly during 24h and more slowly from females than from males. Urines contained less than 11% dose. Mean recoveries during 7 days when 14C was not detectable in the carcass except in one female rat ranged between 93-101%. Biliary excretion of C-14 was prominent (84-91% dose during 24h) in the disposition of C-14 which was also subjected to facile enterohepatic circulation (74% dose). Metabolite profiles in plasma and selected tissues differed. In the former, unchanged dexloxiglumide was the major component whereas in the latter, a polar component was dominant. Urine, bile and faeces contained several C-14-components amongst which unchanged dexloxiglumide was the most important (eg. up to 63% dose in bile). LGMS/MS showed that dexloxiglumide was metabolised mainly by hydroxylation in the N-(3-methoxypropyl)pentyl sidechain and by O-demethylation followed by subsequent oxidation of the resulting alcohol to a carboxylic acid.