Biotransformation of nonionic X-Ray contrast agents In vivo and In vitro

Liposomes loaded with the nonionic iodinated contrast agent iodixanol were injected i.v. into monkeys, rats, and dogs, and liver samples were analyzed by HPLC and mass spectrometry. Two metabolites (M1 and M2), with UV spectra identical to those of the iodixanol isomers (exo and endo) and with a mass increase of 162 compared with iodixanol, were detected. Incubations of iodixanol-liposomes or iodixanol in rat liver homogenates resulted in large amounts of iodixanol metabolites, whereas no metabolites were formed in other organ or tissue homogenates. Four groups of unidentified HPLC peaks were detected: M1 and M2 with a relative retention similar to the metabolite peaks of the in vivo samples, and in addition the minor M3 and M4. UV spectrum analysis indicated that M1 and M3 were structurally related to the iodixanol exo-isomer, whereas M2 and M4 were related to the endo-isomer. Mass spectrometry techniques indicated that the metabolites were conjugates containing one or two hexose residues, which by carbohydrate analysis and experiments with concanavalin A-Sepharose and alpha- and beta-glucosidase were shown to be glucose residues bound to iodixanol through O-alpha1-glycoside-like linkages. Metabolites with similar mass increments also were detected for several other nonionic contrast agents after in vitro incubations in liver homogenates. In conclusion, M1 and M3 are conjugates of the iodixanol exo-isomer with one and two glucose adducts, respectively. M2 and M4 are similar conjugates of the iodixanol endo-isomer. This is the first report on hepatic biotransformation of this class of X-ray contrast agents.