Pharmacokinetics and hepatic disposition of bis[1-( ethoxycarbonyl)propyl]5-acetylamino-2,4,6-triiodoisophthalate in rats and isolated perfused rat livers

Bis[1-(Ethoxycarbonyl)propyl]5-acetylamino-2,4,6-triiodoisophthalate (NC 68 183) was designed as a new computed tomography imaging agent. The purpose o f this study was to determine the pharmacokinetics and metabolism of NC 681 83 in conscious rats and in the isolated perfused rat liver. Animals were i .v. dosed at 69 and 690 mg of iodine/kg. Blood samples were collected at 5, 15, 30, and 60 min, and 7 days after dosing. Tissue samples (liver, kidney , and spleen) were taken at 60 min and 7 days after dosing. NC 68183 was cl eared from blood in first order kinetics following an i.v. administration o f 69 mg l/kg. The volume of distribution (Vss) at steady state and eliminat ion half-life (t(1/2)) were estimated as 24 ml and 11 min. The clearance of NC 68183 from blood was changed to zero-order kinetics following administr ation of 690 mg/kg, and its elimination rate was 16 mu g l/ml.min. The live r and spleen were the only tissues to have the nanoparticle residue at day 7 following administration. NC 68183 (75 mg of agent, 35 mg of I) was injec ted into the isolated perfused rat liver system. Bile flow increased from 1 .0 to 1.3 ml/min/g liver following administration. The biliary excretion ra te maximum was estimated as 11 mg/min/g liver. The metabolite was identifie d using liquid chromatography/mass spectrometry as a monocarboxylic acid pr oduct, which exclusively excreted into the bile in a soluble iodinated meta bolite. Pharmacokinetics data suggested that NC 68183 primarily resides in the blood pool following an i.v. administration with a plasma half-life app ropriate for blood pool imaging.