Potentiometric determination of iodipamide using an iodipamide ion-selective electrode.
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Inhibition by hippurate and probenecid of in vitro uptake of iodipamide and o-iodohippurate. A composite uptake system for iodipamide in choroid plexus, kidney cortex and anterior uvea of several species.
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Animals↗
The choleretic effect of iodipamide.
It is well established that a number of organic anions are excreted by the liver into bile in association with a marked increase in bile flow. Previous studies have shown that iodipamide (3,3'-(adipoyl-diimino)bis[2,4,6-triiodobenzoic acid]), the radiographic contrast material used for intravenous cholangiography, is a potent choleretic. Experiments were performed in unanesthetized dogs to determine if the increased bile flow produced by iodipamide is canalicular or ductular in origin, to quantitate the choleresis associated with iodipamide and taurocholate excretion, and to correlate these findings with the results of in vitro studies in which the osmotic activities of iodipamide and taurocholate in both isotonic saline and bile were determined. The plasma erythritol clearance increase linearly with the excretion of iodipamide, indicating that iodipamide stimulates canalicular bile flow. The choleretic potency of iodipamide (22 ml/mmol) is approximately 3 times that of taurocholate (7.8 ml/mmol), yet the osmotic activity of iodipamide in bile (1.5 mosmol/mmol) is only twice as great as that of taurocholate in bile (0.8 mosmol/mmol). It therefore appears that, per unit of effective osmotic solute secreted, iodipamide carries more water into the bile canaliculi than does taurocholate.
Animals↗
Iodipamide kinetics: capacity-limited biliary excretion with simultaneous pseudo-first-order renal excretion.
Iodipamide was infused into three dogs with bile fistulas to achieve various steady-state blood levels. When using ultracentrifugation techniques, iodipamide was found to be highly bound to plasma protein. The total blood clearance was low relative to hepatic blood flow. For either the whole blood concentration or the unbound concentration of iodipamide, the biliary excretion was shown to be capacity limited with a transport maximum, Tm, of approximately 1.0mumole/kg/min. The steady-state renal excretion rate, plotted against the whole blood concentration of iodipamide, resulted in a concave ascending curve, which could lead to the false conclusion that iodipamide was undergoing active renal tubular reabsorption. However, when corrected for plasma protein binding, a linear relationship was obtained, suggesting that the renal excretion of iodipamide is a pseudo-first-order process. The Michaelis-Menten parameters for the extrarenal elimination, when calculated using the whole blood concentration of iodipamide, led to a similar discrepancy compared to the parameter estimates obtained from biliary excretion rate data. This discrepancy can be eliminated when one uses the unbound concentration of iodipamide in the parameter estimates.
Animals↗
Common properties of hepatocellular uptake of cholate, iodipamide and antamanide, as distinct from the uptake of bromosulfophthalein.
The uptake of iodipamide and of the cyclopeptide antamanide by isolated hepatocytes was reduced reversibly in the absence of oxygen as recently shown for the transport of cholate. Oligomycin, antimycin A and carbonylcyano-chlorophenylhydrazone (CCCP) completely blocked the uptake of iodipamide and antamanide whereas the uptake of cholate was only partially decreased. Reduction of ATP in hepatocytes following replacement of glucose by fructose inhibited the uptake of iodipamide, of antamanide, and also of cholate. In contrast, the penetration of bromosulfophthalein remained unaffected under the above conditions. Arrhenius paralysis yielded high apparent activation energies for the uptake of cholate, iodipamide, and antamanide being 89, 77 and 55 kJ/mol respectively but only 22 kJ/mol for bromosulfophthalein. Mutual transport inhibition was found for iodipamide, antamanide and cholate as well as for bromosulfophthalein. Cholate inhibited the uptake of iodipamide and antamanide competitively. In contrast, bromosulfophthalein inhibited iodipamide uptake in a mixed order fashion. The results suggest a common uptake mechanism for cholate, iodipamide and antamanide different from that of bromosulfophthalein.
Absorption↗
Iodipamide uptake by rat liver plasma membrane vesicles enriched in the sinusoidal fraction: evidence for a carrier-mediated transport dependent on membrane potential.
Iodipamide, a cholecystographic agent, is known to be taken up by isolated hepatocytes by a mechanism similar or identical with the inward transport of bile salts (Petzinger, E., Joppen, C. and Frimmer, M. (1983) Naunyn-Schmiedeberg's Arch. Pharmacol. 322, 174-179). To elucidate its mode of transport, uptake of iodipamide was studied by rapid-filtration techniques on plasma membrane vesicles enriched in the sinusoidal fraction. Uptake was found to be dependent upon the temperature, the intravesicular volume, a gradient of monovalent cations (Na+, K+ or Li+) and the substrate concentration (saturation kinetics with respect to iodipamide: apparent Km = 70 microM, Vmax = 0.31 nmol per mg protein per min at 100 mM NaCl and 25 degrees C). Countertransport and transstimulation in tracer exchange experiments indicate that in vesicles, iodipamide uptake rather than binding occurs. Na+ could be replaced by K+ or Li+ in our system without any effect. However, in the presence of choline chloride a slight, but distinct reduction occurred. Iodipamide uptake was inhibited by cholate, phalloidin, 4,4'-diisothiocyanato-1,2-diphenylethane-2,2'-disulfonic acid and by bromosulfophthalein with inhibition being competitive in the case of cholate and non-competitive in the case of bromosulfophthalein. Alteration of the membrane potential by addition of NO3-, SCN- or SO4(2-) modified the uptake rate for iodipamide. The above results support our earlier hypothesis that the hepatocellular uptake of iodipamide is due to a carrier-mediated transport, probably similar to that of bile acids. However, translocation of iodipamide is assumed to be driven by the membrane potential only and not by Na+ contransport.
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
Effect of iopanoate on the biliary and urinary excretion of iodipamide.
The effect of sodium iopanoate and iopanoic acid on the biliary excretion of iodipamide in dogs was studied. Enteric administration of sodium iopanoate within one hour of iodipamide infusion reduced biliary iodipamide excretion and increased urinary iodipamide output. The biliary and urinary excretion of iodipamide was not influenced by iopanoic acid administered 40 and then again 16 hrs before iodipamide. These results suggest that iodipamide cholangiography can be employed 16-18 hrs after a standard two-day iopanoic acid oral cholecystogram without decreasing the ability to visualize the biliary ductal system or increasing the urinary iodipamide excretion.
Animals↗
Properties of iodipamide uptake by isolated rat hepatocytes.
Exposure of isolated rat hepatocytes to iodipamide resulted in its time dependent accumulation in the cells. No accumulation was observed with rat AS-30D hepatoma cells and isolated jejunal and ileal cells from guinea pig. At concentrations below 75 microM, the iodipamide uptake into the liver cells showed saturation kinetics with a Km of 55 microM and Vmax of 555 pmol/mg cell protein X min. At higher concentrations, a nonsaturable component with a permeability coefficient (P) of 1.02 X 10(-5) cm/s is superimposed on the hepatoselective iodipamide uptake. Uptake in liver cells was partially inhibited by DIDS, an irreversible inhibitor of bile acid and phalloidin uptake in liver cells. Iodipamide uptake was found to be dependent upon Cl- and was slightly reduced in the absence of Na+. Both SCN- and NO3- decreased iodipamide accumulation in liver cells whereas SO4(2-) enhanced the accumulation. As with bile acid and phalloidin uptake, monensin, valinomycin and gramicidin A markedly reduced iodipamide uptake in rat hepatocytes. The results support the hypothesis that the organotropic excretion of iodipamide is partially performed by an energy dependent carrier which is the bile acid transporter of hepatocytes.
Animals↗
The effect of bilirubin on biliary iodipamide excretion in the dog.
The effect of bilirubin on biliary iodipamide excretion and concentration was investigated in cholecystectomized dogs during complete bile diversion and constant bile salt replacement. A significant dose-dependent depression of both biliary iodipamide excretion rate and bile iodipamide concentration was found with increasing bilirubin dose. Whether or not bilirubin was infused at a constant of 0.1 mu moles/min/kg, the excretion rate and bile concentration of iodipamide was greatest with the largest 5.2 mu moles/min/kg iodipamide dose. Iodipamide had no significant effect on the bilirubin excretion rate, but because of its highly choleretic nature it had a dilution effect on the bilirubin bile concentration. This investigation suggests that a reduction of the iodipamide blood levels by either decreasing the dose or prolonging the infusion time will lead to poorer radiographic visualization of the biliary system in patients with unconjugated hyperbilirubinemia (prehepatic jaundice).
Animals↗
In vitro uptake of bile acids by choroid plexus, kidney cortex and anterior uvea. I. The iodipamide-sensitive transport systems in the rabbit.
Renal cortex, anterior uvea, lateral choroid plexus and terminal ileum accumulate -14C-cholate, glycocholate, deoxycholate and chenodeoxycholate to considerable tissue/medium ratios. Iodipamide partly inhibits accumulation by kidney, uvea and plexus but not ileum. In renal cortex the sensitive part is similar to 10, 60 and 90 percent for dihydroxy acids, cholate and glycocholate respectively. Hippurate depresses uptake in kidney and uvea but hardly in plexus. Simultaneous uptake by renal cortex and uvea of -14C-cholate or glycocholate, -125I-iodipamide and -131I-o-iodohippurate was studied with unlabelled iodipamide and hippurate as inhibitors. The concentration-dependence of the inhibition required the assumption of 4 partly overlapping iodipamide-sensitive transport systems handling the 4 test substances: the hippurate (H)-system, one moderately (L(1)) and one very hippurate-resistant (L(2)) part of the liverlike L-system and a fourth system called BS, more evenly inhibitable by iodipamide and hippurate than the others. The L(2)-system carries iodipamide but very little bile acids. No iodipamide-sensitive system clearly specialized for bile acid transport was found. The systems have only moderate affinity for bile acids and probably treat them just as large organic anions. A new mathematical procedure to test the degree of complexity of composite transport systems without kinetic assumptions was used.
Animals↗
The role of serum albumin in the hepatic excretion of iodipamide.
The contrast agent for biliary tract visualization, iodipamide, is strongly bound to serum albumin. The relationship between the affinity of the contrast agent for albumin and its preferential uptake and excretion by the liver has been unclear. The role of serum albumin on hepatic uptake and excretion of iodipamide therefore was investigated on the isolated perfused rabbit liver. With the perfusate containing fully reconstituted rabbit plasma protein or 3.5 g/100 ml rabbit albumin alone, the iodipamide excretion is initially extremely slow. It then increases gradually to about 6 mug/gm liver per min by 60 minutes and thereafter remains constant. The half-time of transfer to the bile is about 130 min. Without albumin in the perfusate the initial clearance rate of iodipamide is rapid, with half-time transfer to the bile of about 40 min. Rabbit serum globulins have no effect on iodipamide excretion. Thus, binding of iodipamide to albumin retards the transfer of iodipamide from plasma to the bile, probably due to competition between albumin and the anion binding protein of the liver.
Animals↗
Biliary excretion of iodipamide.
Conflicting data have been reported concerning the optimum dose and rate of administration of iodipamide required to obtain maximum radiographic opacification of the biliary tree during intravenous cholangiography. Experiments were performed in dogs to determine the effect of plasma concentration on the excretion and concentration of iodipamide in the bile and urine during a steady state of infusion and excretion. The data indicate that a hyperbolic relation exists between the plasma concentration and both the biliary concentration and the total biliary excretion. A mathematical expression of these relations is presented. At low plasma concentrations, iodipamide was not excreted in the urine. However, at high plasma concentrations, urinary excretion increased sharply. It appears that a biliary concentration of iodipamide sufficient to achieve adequate radiographic visualization of the biliary tree can be obtained without significant renal excretion by constant infusion of iodipamide at an appropriate rate in dogs. Stepwise increase in the infusion rate until adequate radiographic visualization is obtained may be the best method for performing intravenous cholangiography to obtain visualization with the least amount of iodipamide in order to minimize toxicity.
Animals↗
The effect of sodium taurocholate on biliary iodipamide excretion in the dog.
The effect of sodium taurocholate in stepwise increasing infusion rates, 0.3 to 9.6 mumoles per min per kg, on the biliary excretion rate of iodipamide was investigated in 6 dogs (10 experiments) with complete bile diversion under general anesthesia. Iodipamide was administered intravenously with an initial priming dose of 33 mumoles per kg followed by a constant infusion of 1.3 mumoles per min per kg. Although the bile flow continuously increased with an increasing taurocholate dose, the iodipamide excretion rate reached a plateau with a 0.6 mumoles per min per kg of taurcholate infusion, which was 20% higher than with the lowest taurocholate dose. With a taurocholate dose over 2.4 mumoles per min per kg, a significant decrease in the iodipamide rate was found, amounting to 22% of its maximum value with the largest taurocholate dose. The bile iodipamide concentration was already at its maximum with the lowest taurocholate dose, and it decreased with an increasing taurocholate dose. Since the bile iodipamide concentration is probably the most important determinant in clinical cholangiography, low bile salt plasma levels should result in the best radiographic visualization of the biliary tree.
Animals↗
Saturation kinetics of iodipamide.
To characterize the saturation kinetics of iodipamide, timed samples of blood, urine, and bile were taken from two unanesthetized dogs infused with iodipamide at increasing rates to achieve various steady state blood concentrations. Biliary excretion rate of iodipamide reached an asymptote with increasing blood concentration, indicating a biliary transport maximum (Tm) of 15.2 to 16.2 mgI/min. Urinary excretion was not a pure, first order process and urinary excretion rate was higher than the glomerular filtration rate corrected for plasma protein binding, suggesting that active tubular secretion may play a part. Extrarenal elimination followed Michaelis-Menten kinetics. Estimates of maximum rate (Vm) and Michaelis-Menten constant (Km) were obtained graphically. The estimated values of Vm were 4 to 6 times that of biliary Tm. In acute infusion experiments the iodipamide excreted in the bile and urine and that remaining in the organs analyzed accounted for only a fraction of the dose administered; no significant accumulation of iodipamide was found in the liver.
Animals↗
Effects of iodipamide on human C3 and factor B in vitro.
The effects of iodipamide on C3 and factor B in normal human serum and in purified form have been examined by immunoelectrophoresis and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Temperature-dependent changes in immunoelectrophoretic profiles have been observed; however, these are not the same as those obtained after treatment of normal human serum (NHS) with cobra venom factor Naja naja. Analyses of iodipamide-treated NHS and purified C3 and factor B by reducing SDS-PAGE indicate that no macromolecular changes have occurred in C3 and factor B that can be ascribed to proteolysis (i.e., activation). The changes observed in C3 and factor B, including loss of hemolytic activity, appear to be due to direct interactions between iodipamide and C3 and factor B. In the case of factor B, iodipamide treatment at 37 degrees C induces aggregation, which is reversible upon reduction with beta-mercaptoethanol.
Complement Activation↗
The liver-like anion transport system in the rabbit uvea does not eliminate iodipamide from the eye.
Iodipamide is known to be actively taken up in vitro by the rabbit iris-ciliary process preparation. This uptake is partly resistant to high concentrations of hippurate and the resistant part has been called the 'liver-like' system. In vivo iodipamide is eliminated from the rabbit eye after injection into the vitreous by a saturable process. This process is hippurate-sensitive and no role for any hippurate-resistant system was found. Two explanations for the discrepancy between the results in vitro and in vivo are offered: (1) Iodipamide may be a less than perfect model substance for physiological compounds that normally are transported by a liver-like system from the vitreous cavity and the posterior aqueous humour to the blood. (2) Iodipamide is a model for compounds that are taken up by the non-pigmented epithelium of the ciliary processes by a liver-like system and transported to the pigmented epithelium for metabolic modification.
Animals↗
Iodipamide hepatotoxicity in the rat.
Iodipamide meglumine (Cholografin) has been implicated in several cases of liver injury in patients. The present study was designed to assess the hepatotoxic potential of this drug in rats. Iodipamide administered intraperitoneally or intravenously caused a characteristic type of necrosis which began in the midzonal area and spread to the centrilobular region. Only rats weighing 400 g or more developed necrosis when the dose administered was 2 mmol/kg. Rats weighing 200 g failed to develop liver necrosis even when given 3 mmol/kg. Selenium deficiency and pretreatment with 3-methylcholanthrene protected against liver necrosis due to iodipamide. Phenobarbital pretreatment provided little or no protection. Kidney tubular necrosis was also observed but occurred in young rats and in selenium-deficient rats which developed no liver necrosis. These results indicate that iodipamide is a hepatotoxin in rats. There are a number of factors, age being the most striking, that modify its hepatotoxicity.
Age Factors↗
A case of meglumine iodipamide hepatotoxicity.
There have been only two reports of severe hepatotoxic reaction caused by meglumine iodipamide. Lately we experienced such a reaction in an 66-year old female with chronic intrahepatic cholestasis. After drip infusion cholangiography was performed by infusing 40 ml. of 50% meglumine iodipamide (Biligrafin) intravenously, the patient developed nausea and abdominal pain. Her serum transaminase rose to more than 2,000 K-A units on the third day and gradually returned to normal by the 18th day. The macrophage migration inhibition test of her blood was positive for meglumine iodipamide. Accordingly some delayed type of hypersensitivity in the above reaction could be considered. When a larger amount than a recommended dose of meglumine iodipamide is infused in cholangiography, a severe hepatotoxic reaction might be induced, especially in icteric cases.
Aged↗