Iopronic acid

In contrast to the 2,4,6-triiodobenzoic acids, substituted alkanoic and alkoxyalkanoic acids containing a 2,4,6-triiodophenyl or a 2,4,6-triiodophenoxy group with open position 5, such as iopanoic acid, tyropanoate, iogly-camic acid, and iopronic acid, have both lipophilic and hydrophilic properties. These contrast acids have an acidity constant about two units higher than that of the water-soluble, fully substituted 2,4,6-triiodobenzoic acids (263) and are not completely ionized at the physiological pH. In the nonionized form, the contrast molecules can be absorbed and transported across cell membranes after oral administration. 

The chemical (3) and pharmacological (4) properties of iopronic acid have been described. 

Preliminary vitro experiments were carried out using rat liver homogenates, the 9000 g supernatant and microsomes. These experiments revealed that iopronic acid is metabolized by microsomal enzymes with consumption of NADPH and oxygen (5). Thin layer... 

FIG. 2. Metabolism of iopronic acid with rat liver microsomes. 

Interpretation of the mass spectrum (M5) of iopronic acid (Fig. 3) and its methyl ester provides a rationalization of a number of fragmentations as shown in Fig. 4. Comparison of the MS of M2 (Fig. 5) its methyl ester (Fig. 6) and Mi (Fig. 7) with these of iopronic acid and its methyl ester indicated that M2 was 3-acetamido-2,4,6-triiodophenoxyacetic acid and Mi. was hydroxy-ethyl (3-acetamido-2,4,6-triiodophenyl)ether. Confirmation of the structures suggested for the two metabolites was obtained by... 

FIG. 4. Mass spectral fragmentations of iopronic acid and its methyl ester. 

The phenol ether bond appears to resist enzymatic cleavage since 3 acetamido 2,4,6-triiodophenol was not detected as a metabolite. Also important is the observation that the metabolites do not include de-iodinization products. Oral administration of iopronic acid in amounts of 100 mg/kg to Wistar rats is followed by excretion of products containing iodine representing 13% (as iodine) in the urine and 61% in the faeces over the first 24 hrs (6). When the same dose is given intravenously to cannulated rats, 8% is excreted in the urine and 82% in the bile in the first 3 hours. 

The urine of rats which had been administered iopronic acid was shown, by means of TLC and high pressure liquid chromatography (HPLC) to contain 4 iodinated metabolites together with the original compound. Two of these were identical with M2 and mentioned previously. 

The other two metabolites identified (Mi and Mg) are glucuronic acid conjugates since hydrolysis by B-glucuronidase produces iopronic acid (M3) and 2-hydroxylethyl(3-acetamido-2,4,6-triiodo-phenyl)ether (Mi ) respectively. The structure of Mg was confirmed by TLC, HPLC and by comparison with an authentic sample prepared as shown in Fig. 10. The mass spectrum of Mg is shown in Fig. 11. 

Enz3nnatic hydrolysis with ""glucuronidase gave glucuronic acid and iopronic acid from either metabolite. 

On the other hand alkaline hydrolysis resulted in the formation of glucuronic and iopronic acid from Mi and iopronic acid and an unidentified saccharic acid from M5. Elemental analysis IR, NMR and MS data are consistent with the structure proposed for Mi (Fig. 13) although comparison with an authentic sample could not be carried out. 

Oral administration of 3 g of iopronic acid to human subjects resulted in the urinary excretion of 71% (average of six measurements) of the administered dose in the first 48 hours (9). Two subjects were tested for faecal excretion until the faeces were free of iodine-containing compounds. The total excretion amounted to 7.3% in one case and 9% in the other. In addition to iopronic acid (M3) the urine of the volunteers contained M2, Mi and Ml Fig. 14 illustrates the metabolic fate of iopronic acid in man with the relative amount of each metabolite in the urine over 48 hours. 

The only detectable compound in the faeces was iopronic acid. The small amount of iopronic acid recovered in the faeces reflects a remarkably thorough intestinal absorption of this compound. At the same time the roentgenograms obtained with iopronic acid demonstrate a marked biliary excretion of the compound, this conflicts with the limited faecal excretion observed unless one supposes a massive intestinal absorption followed by urinary excretion of the glucuronic acid conjugate of iopronic acid. A summary of the metabolism of iopronic acid in the three species studied is given in Fig. 15. 

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