Iotroxic acid

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

abstract

Qualifier:

no guideline followed

GLP compliance:

not specified

Radiolabelling:

yes

Remarks:

131I-labelling

Species:

other: human

Sex:

not specified

Route of administration:

other: injection

Vehicle:

not specified

Positive control reference chemical:

N.A.

Details on study design:

The biotransformation of the 131I-labeled cholegraphic media iotroxic acid in man is investigated. Plasma, urine and fistular bile were analyzed for unchanged and metabolized constituents of the administered substances using thin layer chromatography.

Details on dosing and sampling:

N.A.

Statistics:

N.A.

Metabolites identified:

yes

Details on metabolites:

No metabolites were found in plasma, but up to two were found in urine in addition to unchanged contrast media (a total of 50% of the total elimination in 24 h urine). A metabolite was only found in the fistular bile after the injection of iotroxic acid.

Conclusions:

The biotransformation of the 131I-labeled cholegraphic media ioglycamic acid, iodoxamic acid and iotroxic acid in man is investigated. Plasma, urine and fistular bile were analyzed for unchanged and metabolized constituents of the administered substances using thin layer chromatography. No metabolites were found in plasma, but up to two were found in urine in addition to unchanged contrast media (a total of 50% of the total elimination in 24 hr. urine). A metabolite was only found in the fistular bile after the injection of iotroxic acid.

Executive summary:

The biotransformation of the 131I-labeled cholegraphic media ioglycamic acid, iodoxamic acid and iotroxic acid in man is investigated. Plasma, urine and fistular bile were analyzed for unchanged and metabolized constituents of the administered substances using thin layer chromatography. No metabolites were found in plasma, but up to two were found in urine in addition to unchanged contrast media (a total of 50% of the total elimination in 24 hr. urine). A metabolite was only found in the fistular bile after the injection of iotroxic acid.

Reference 2

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

abstract

Objective of study:

excretion

Qualifier:

no guideline followed

GLP compliance:

not specified

Radiolabelling:

not specified

Species:

rat

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

Tissue: rat liver

Route of administration:

other: in vitro

Vehicle:

not specified

Duration and frequency of treatment / exposure:

not specified

Control animals:

not specified

Details on study design:

Mechanisms involved in the biliary excretion of organic anions were investigated in hemoglobin-free perfused rat liver using IX-acid as a test substance. The elimination of IX-acid from the perfusate, biliary excretion and the amount of IX-acid in the hepatocytes was investigated. Further, influence of the transport of IX-acid in the presence of Bromsulphalein and Dexamethasone-21-sulfate should give information on biliary transport mechanisms of organic anions in liver.

Details on excretion:

Elimination of iotroxic acid from the perfusate into the hepatocytes followed first-order kinetics, indicating the process to be that of passive diffusion. Though the biliary excretion occurred rather rapidly, the amount of iotroxic acid in the hepatocytes increased with increases in the initial concentration in the perfusate and approached a maximal amount of ca. 2.8 mu moles/g wet weight of liver. The maximal values observed for the biliary concentration and the rate of biliary transport were 20-24 mM and 38-48 nmoles/min . g liver, respectively

Metabolites identified:

not measured

Elimination of iotroxic acid from the perfusate into the hepatocytes followed first-order kinetics, indicating the process to be that of passive diffusion. Though the biliary excretion occurred rather rapidly, the amount of iotroxic acid in the hepatocytes increased with increases in the initial concentration in the perfusate and approached a maximal amount of ca. 2.8 mu moles/g wet weight of liver. The maximal values observed for the biliary concentration and the rate of biliary transport were 20-24 mM and 38-48 nmoles/min. g liver, respectively. Bromsulphalein inhibited the diffusion of iotroxic acid into the hepatocytes whereas accumulation of iopodic acid in the hepatocytes produced an inhibition of diffusion into the hepatocytes and transport into the bile. Dexamethasone-21-sulfate (DXMS) was transported rapidly into the bile, but in the presence of iotroxic or iopodic acids, excretion of DXMS into the bile was inhibited, while diffusion into the hepatocytes was inhibited only by iopodic acid. The competition observed with those substances demonstrates the presence of a common mechanism for the biliary transport of organic anions in the liver.

Conclusions:

The study indicates, that IX-acid will be eliminated into the hepatocytes following first-order kinetics, indicating the process to be that of passive diffusion. Biliary excretion of IX-acid occurred rapidly, but an increase of the initial concentration of IX-acid, the amount of IX-acid also increased in the hepatocytes and approached to a maximal amount

Executive summary:

Elimination of iotroxic acid from the perfusate into the hepatocytes followed first-order kinetics, indicating the process to be that of passive diffusion. Though the biliary excretion occurred rather rapidly, the amount of iotroxic acid in the hepatocytes increased with increases in the initial concentration in the perfusate and approached a maximal amount of ca. 2.8 mu moles/g wet weight of liver. The maximal values observed for the biliary concentration and the rate of biliary transport were 20-24 mM and 38-48 nmoles/min. g liver, respectively. Bromsulphalein inhibited the diffusion of iotroxic acid into the hepatocytes whereas accumulation of iopodic acid in the hepatocytes produced an inhibition of diffusion into the hepatocytes and transport into the bile. Dexamethasone-21-sulfate (DXMS) was transported rapidly into the bile, but in the presence of iotroxic or iopodic acids, excretion of DXMS into the bile was inhibited, while diffusion into the hepatocytes was inhibited only by iopodic acid. The competition observed with those substances demonstrates the presence of a common mechanism for the biliary transport of organic anions in the liver.

Reference 3

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

abstract

Objective of study:

excretion

Qualifier:

no guideline followed

GLP compliance:

not specified

Species:

rat

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

tissue: hemoglobin-free perfused rat liver
Observation of pharmacokinetic profile in vivo

Route of administration:

not specified

Vehicle:

not specified

Details on exposure:

not specified

Duration and frequency of treatment / exposure:

not specified

Control animals:

no

Positive control reference chemical:

N.A.

Details on study design:

Pharmacokinetical properties of eight triiodobenzene derivatives, X-ray contrast agents (IX-acid, Iodipamic acid, Iodoxamic acid and Ioglycamic acid), were studied in the hemoglobin-free perfused rat liver with emphasis on the structural relation to biliary transport. The diffusion into hepatocytes, accumulation in the cells and active transport into the bile of several X-ray contrast agents, including IX-acid were determined and compared with the pharmacokinetically profile observed in vivo.

Details on dosing and sampling:

N.A.

Statistics:

N.A.

Metabolites identified:

not measured

Pharmacokinetical properties of eight triiodobenzene derivatives, X-ray contrast agents, were studied in the hemoglobin-free perfused rat liver with emphasis on the structural relation to biliary transport. With chemical modification of the basic structure, these agents showed different characteristics in the processes of diffusion into hepatocytes, accumulation in the cells and active transport into the bile, and were separated into four groups; [I]: Iotroxic acid (1), Iodipamic acid (2), Iodoxamic acid (3), and Ioglycamic acid (4) which showed faster rates of diffusion into hepatocytes [(1) greater than or equal to (2) greater than (3) greater (4)] and also of biliary excretion [(1) greater than (2) greater than (4) greater than (3)], [II]: Diatrizoic acid and Metrizamide showed poor diffusion and biliary excretion, [III]: Iopodic acid showed the highest permeability into and accumulation in hepatocytes with little biliary excretion, [IV]: ZK73 215 was slowly transported into the bile, yet, showed little permeation through the cell membrane. Characteristics of (1), (2) and (3) observed in the perfused liver were, in principle, confirmed in the pharmacokinetical profile observed in vivo. However, the fast diffusion of (2) into the hepatocytes appears to be hampered by high binding ability with serum proteins, whereas the relatively poor profile of the biliary excretion of (3) was improved by its low protein-binding in blood in vivo. Superiority of (1) as a cholangiographic agent was demonstrated by the fast biliary excretion in both the case of experimental systems and moderate protein-binding.

Conclusions:

This study indicates, that IX-acid will be rapidly diffused into hepatocytes as well as fast excreted biliary with a moderate protein-binding.

Executive summary:

Biliary excretion of several X-ray contrast agents were investigated in the hemoglobin-free perfused rat liver and the results confirmed by the pharmacokinetical profile observed in vivo. In comparison to the other X-ray contrast agents,

IX-acid showed the fastest rates of diffusion into hepatocytes and biliary excretion compared to the other X-ray contrast agents as well as a moderate protein binding in vivo.

Description of key information

Suitable data is available for the target substance Iotroxic acid an bilary excretion. In the publication by Mützel et al., 1976 the biotransformation of the 131I-labeled cholegraphic media ioglycamic acid, iodoxamic acid and iotroxic acid in man was investigated. Plasma, urine and fistular bile were analyzed for unchanged and metabolized constituents of the administered substances using thin layer chromatography. No metabolites were found in plasma, but up to two were found in urine in addition to unchanged contrast media (a total of 50% of the total elimination in 24 hour urine). A metabolite was only found in the fistular bile after the injection of iotroxic acid. In the studies by Azuma, 1980 biliary excretion of several X-ray contrast agents were investigated in the hemoglobin-free perfused rat liver and the results confirmed by the pharmacokinetical profile observed in vivo. In comparison to the other X-ray contrast agents, IX-acid showed the fastest rates of diffusion into hepatocytes and biliary excretion compared to the other X-ray contrast agents as well as a moderate protein binding in vivo.