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Twenty-one anicteric patients with a t-tube in situ were studied between the ninth and 11th postoperative days. Eleven patients were given an intravenous infusion of the biliary contrast agent ioglycamide (Biligram), while the other 10 acted as controls. Bile flow was recorded and the biliary concentrations of ioglycamide, bile salt, phospholipid, and cholesterol estimated in the two groups. The biliary excretion of ioglycamide was associated with a significant choleresis which was probably due to the obligatory coupling of the osmotically active contrast agent molecules with water. Biliary ioglycamide excretion did not significantly alter bile salt secretion rates. In contrast, the biliary secretion of both phospholipid and cholesterol was significantly lowered (P less than 0.001). Unlike chenodeoxycholic acid, ioglycamide significantly reduced bile acid independent cholesterol secretion (P less than 0.01), although secretion rate in terms of mumol of bile acid was essentially unchanged.

The bile acid taurocholate increases the biliary excretion of organic anions, such as sulfobromophthalein (BSP), bilirubin and iopanoic acid. In the present study has been investigated the effect of taurocholate on 1. Canine biliary excretion and concentration of the i.v. contrast medium ioglycamide and 2. Canine bile flow. The experimental model consisted of cholecystectomized, anaesthetized dogs with a fistula, through which the common bile duct could be catheterized and drained. One hour after cannulation, i.v. infusion of ioglycamide at a rate of 4 mumol/min./kg. was started. Two hours after the infusion start a control group received i.v. infusion of saline, while in another a 1.5% sodium taurocholate infusion was started with stepwise increases with 30 min. intervals from 0.4 to 0.8, 1.6 and 3.2 mumol/min./kg. Compared with control, all rates of taurocholate infusion increased bile flow and decreased biliary ioglycamide concentration. Although the bile flow with increasing taurocholate infusion rates was enhanced, the biliary ioglycamide excretion did not increase. The results indicate that ioglycamide and taurocholate are excreted into bile by separate excretion mechanisms. As taurocholate increases the biliary excretion of some other organic anions, it supports the hypothesis that organic anions are excreted into bile by more than two excretion mechanisms, taurocholate affecting only some of them.

The concentration of iodine in the bile of patients with indwelling T-tubes has been measured following administration of the new cholangiographic agent Iotroxamide. Studies have been performed after administration of the contrast agent by both 10 min bolus injection and 1 h drip infusion techniques. Comparison has been made with the iodine concentrations obtained after administration of equimolar amounts of Ioglycamide. There was no significant difference in the biliary iodine levels obtained with the two methods of administration when Iotroxamide was the contrast agent employed. However, with Ioglycamide the slow infusion technique produced higher iodine levels than the bolus injection method (P less than 0.05). Comparison between the two agents reveals that, whichever administration technique is used, Iotroxamide provides higher iodine levels than Ioglycamide. After bolus injection the superiority for Iotroxamide is in the region of 20% and after slow infusion is of the order of 10--15%. It is concluded that Iotroxamide is likely to prove superior to Ioglycamide as a cholangiographic agent. In terms of opacification of the biliary tree there is little to choose between bolus injection and slow infusion techniques when using Iotroxamide and the relative toxicity of the two techniques should be the major factor in determining which method is employed in clinical practice.

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.

The biliary and urinary excretion and the choleretic effect of ioglycamide were studied in unanesthetized bile fistula dogs using stepwise increasing infusion rates to obtain multiple steady states. The results are compared with data from previously reported experiments in the same animals using iodoxamate and iodipamide. The rate of biliary excretion and the choleretic effect of ioglycamide are similar to those of iodipamide and iodoxamate. Like iodipamide and iodoxamate, the relation between infusion rate or plasma concentration and biliary excretion or concentration of ioglycamide are hyperbolic and can be fitted to saturation kinetics. Quantitatively, the excretion of ioglycamide and iodipamide are virtually identical. However, for any equimolar infusion rate or plasma concentration, more iodoxamate than ioglycamide is excreted in the bile. Despite the greater biliary excretion of iodoxamate, the maximum biliary concentration of ioglycamide, iodipamide, and iodoxamate is the same at low basal bile flow because the choleretic effects of the three compounds are equal. The data suggest that, theoretically, with any equimolar dose ioglycamide will be identical to iodipamide as a contrast material for intravenous cholangiography, but that iodoxamate may be superior to ioglycamide because more iodoxamate is excreted in the bile. This advantage of iodoxamate might become apparent clinically in patients with high basal bile flow or if smaller doses of the contrast material are used. However, at the presently recommended doses of the two compounds, it is unlikely that the use of ioglycamide for intravenous cholangiography will be any different than iodoxamate.

Theophylline (TH), which has been shown in experimental dogs to increase bile-salt-independent bile flow, was studied in its effect on the biliary excretion and concentration of the intravenous contrast medium ioglycamide in cholecystectomized anesthetized dogs equipped with a Thomas cannula through which the common bile duct could be cannulated. One hour after cannulation, i.v. infusion of ioglycamide at the rate of 4 mol/min/Kg was started. Two hours later, 10 mg/kg of TH was injected intravenously and the experiment continued for a further 75 minutes. Bile was collected at 15 min. intervals throughout the whole experiment and simultaneous intravenous blood samples were taken. In this study, TH increased bile flow and decreased biliary ioglycamide concentration. Although TH increased bile flow, it had no effect on the biliary excretion of ioglycamide. It may be postulated that the organic anion ioglycamide, and possibly other organic anions, are secreted into the bile by mechanisms, unaffected by drugs which increase bile-salt-independent bile flow in a similar manner to TH.

The excretion of ioglycamate in the bile of the rhesus monkey was measured at 5% and at 100% bile diversion following an intravenous bolus injection of ioglycamate. At 100% diversion the bile volume was reduced and the concentration of ioglycamate was increased, but the quantity excreted was unchanged. A similar study using iodipamide reported previously gave the same result. When the ioglycamate was given by intravenous infusion, the effect of 100% bile diversion was quite different. The concentration of ioglycamate in the bile was unchanged by the bile diversion but the excretion was reduced. These results indicate that the transport maximum for the excretion of ioglycamate in bile is not a constant and is reduced by interruption of the enterohepatic circulation of bile salts. The maximum concentration of ioglycamate in bile was constant and was independent of the reduction in bile salt output produced by 100% bile diversion. Following a single bolus injection however, the reduction in bile flow produced by 100% bile diversion increased the biliary concentration of ioglycamate. These results suggest that the excretion of ioglycamate is limited by a maximum concentration rather than a transport maximum. The maximum rate of transport (Tm) is dependent on two factors--the maximum concentration of ioglycamate in the bile and the rate of bile flow. The maximum concentration is achieved by an infusion technique and not by a single bolus injection and this supports the view that an infusion technique should be used for intravenous cholangiography.

Iodine-131 labelled Biligram has been evaluated as a radiopharmaceutical for dynamic scintiscanning of the liver and biliary tract. In 10 normal subjects there was good visualisation of the liver and gallbladder. In 18 patients 131I Biligram was found to be unsatifactory for differentiating parenchymal liver disease from biliary tract obstruction owing to inability to demonstrate the gallbladder when liver function was more than mildly deranged. Quantitative analyses of blood clearance and hepatic activity curves for 131I Biligram were not clinically helpful. Urinary excretion of 131I Biligram increased with the degree of hepatic dysfunction.

Plasma ioglycamide concentration was linearly related to the rate of intravenous infusion over a dose range of from 1 to 4 mg per kg per min. The relation between plasma and biliary concentration of ioglycamide was studied in 15 anicteric patients with a T-tube in situ. Peak biliary concentrations and excretory rates of ioglycamide were seen when the plasma concentration was greater than 1500 micrograms per ml. The mean biliary transport maximum (Tm) for ioglycamide in man was 31.6 mg/min (range 22.0-40.4). The results suggest that near optimal concentrations of iodine in the bile duct can be obtained during intravenous cholangiography if ioglycamide is infused for one hour at a rate of about 4 mg per kg per min.

The influence of a phenobarbital pretreatment on the distribution and biliary excretion of Ioglycamide was studied in 6 experiments in the anaesthetized minipig. The phenobarbital pretreatment led to a significant increase of the biliary transportmaximum and the biliary concentration of Ioglycamide. A detailed analysis suggests a phenobarbital induced stimulation of the hepatocellular excretion. The applicability of a pretreatment with phenobarbital in order to improve the opacification of the biliary system during x-ray-examinations with Ioglycamide is discussed.

16 experiments were performed in order to investigate the mechanisms of biliary excretion of Ioglycamide in the mini-pig. The results confirm the mechanisms known from other species for this experimental animal. Additionally, however, they demonstrate a significant linear correlation between the spontaneous bile flow and the biliary transport-maximum of Ioglycamide. It is concluded that this correlation is due to the fact that the bile flow as well as the transport-maximum represent independent parameters of the excretory capacity of the liver cells. This conclusion is supported by further experiments that were unable to show an improvement of the biliary transport-maximum of Ioglycamide by stimulation of the bile flow during infusions of bile acids and secretin. These results prove the impossibility to enhance the biliary excretion of Ioglycamide by stimulation of bile flow. This, however, indicates that it is possible to dilute or concentrate the biliary Ioglycamide concentration by induced variations of bile flow, a fact that might become important to improve the efficiency of i.v. cholegraphy.

In a total of 532 patients, Bilivistan and Endomirabil are compared in cholecystography regarding side effects and visualization. Endomirabil clearly demonstrates the advantage of better tolerance. It is shown that slow and constant injection leads to a decrease in the rate of adverse reactions and improvement of radiographic demonstration.

Pharmacokinetic data after injection of the new cholegraphic contrast medium iotroxic acid (Biliscopin) in man are reported and compared with the results of injections of ioglycamate and iodoxic acid. Iotroxic acid is less completely bound to plasma proteins than ioglycamate, but significancy more so than iodoxamate. Plasma protein binding depends on contrast concentration in the plasma, as does excretion in the urine. Biliary transport rate and maximal iodine concentration in the gall bladder are higher after injections of iotroxinate and iodoxamate than after ioglycamate.

Loops of small intestine in seven rabbits were resected with intact pedicle and ligated at both ends after instillation of 0.5 ml of Gastrografin, Urografin 76%, Amipaque 370 mg I/ml, Amipaque 170 mg I/ml or physiologic saline. After half an hour, the amount of fluid in the loops containing Gastrografin and Urografin 76% increases about twice as much as in the loops containing Amipague with the same iodine concentration because of their greater osmolality. The differences between the loops with isotonic Amipaque (170 mg I/ml) and physiologic saline are not significant. Precipitation occurs when sodium and meglumine salts of diatrizoate, metrizoate, iothalamate, iocarmate and ioglycamate are mixed with 0.05 N HCl. No precipitation occurs with Amipaque, not even when the HCl concentration is as high as 1.2 N. Precipitation occurs when Gastrografin is added to gastric juices with low pH, but is not seen with Amipaque should be a suitable contrast medium for gastrointestinal examinations because of its low osmolality and toxicity and good solubility in gastric juice.

The present study reports on the effect of glucagon on the excretion of ioglycamate in experimental intravenous cholangiography on dogs. Glucagon increased the bile flow rate highly significantly (p < 0.001). At the same time the concentration of the contrast medium decreased highly significantly (p < 0.001). The biliary tree output of the contrast medium also increased, this increase was not statistically significant. This investigation suggests that glucagon seems to have effect on the bile flow as well as on the output of contrast medium in experimental cholangiography.

The effect of furosemide on biliary excretion of ioglycamide and bile flow during experimental cholangiography was studied in cholecystectomized and anaesthetized dogs equipped with a Thomas cannula through which the common bile duct could be cannulated. Ioglycamide infusion was started one hour after cannulation of the common bile duct, the infusion rate being 4 micromol/min/kg. Two hours later, 2 mg/kg furosemide was injected intravenously. After furosemide administration biliary ioglycamide concentration and bile flow remained the same as before the furosemide administration. Our evidence suggests that furosemide has no effect on the biliary excretion of ioglycamide or bile flow during ioglycamide cholangiography on dogs.

When five patients with varying degrees of hepatic impairment and a T-tube in situ were given intravenous ioglycamide at a rate of 2 mg/kg/min for two hours the mean biliary excretion in the first two hours was only 3.2% of the administered dose. In contrast, in five T-tube patients with relatively normal liver function the mean biliary excretion over the same time interval was 20.6%. The mean plasma concentration of ioglycamide achieved at the end of a two-hour intravenous infusion at 2 mg/kg/min was 1427 +/- 187 microgram/ml in six anicteric patients and 1262 +/- 82 in six jaundiced patients. Despite these very similar plasma levels the 24-hour urinary excretion of ioglycamide was 42.3 +/- 3.8% of the administered dose in the patients with jaundice compared with only 18.1 +/- 2.4% in the anicteric group. These differences probably reflect the fact that the percentage of unbound contrast agent in the plasma of the jaundiced group (11.9 +/- 1.9%) was significantly higher than that of the anicteric group (6.4 +/- 0.9%). It is suggested that bilirubin and possibly other substances in the plasma are competing with ioglycamide for binding sites on albumin. These factors need to be borne in mind when performing intravenous cholangiograms on jaundiced patients.

Twenty-five intravenous cholangio-cystograms were carried out in children aged 2 to 15 years (10 by injection, 15 by infusion). Total bilirubin, GOT, GPT, GLDH and alkaline phosphatase were determined before and after injection of the contrast medium. The contrast media used were "Biligram for infusion" (17%) and "biligram for injection" (35%). Contrast dose per kilo body weight depends on the age of the patient: a) For infusion: infants 1.6 ml/kg/KG, small children 1.2 ml/kgKG, older children 0.8 ml/kg/KG. b) for injection: infants 0.8 ml/kg/KG, small children 0.6 ml/kg/KG, older children 0.4 ml/kg/KG. Both methods, in the above doses, provided good demonstration of the biliary tree and gall bladder. Films were taken at 30 minutes, 60 minutes and 90 minutes after the end of the injection, and 40 minutes after a fatty meal. No allergic reactions were observed, nor any effect on the liver enzymes.

The maximun rate of excretion of ioglycamate in the bile of the rhesus monkey was achieved when the rate of adminstration was at least twice the rate of excretion. A maximum concentration of ioglycamate in the bile was also established, and this is more important to the visualization of the bileducts than the quanity of ioglycamate excreted. The maximum concentration was obtained at the same rate of infusion as that which produced the maximum rate of excretion. The peak concentration was sustained longer with an infusion lasting two hours than with one lasting 36 minutes, althought the same quanity of ioglycamate had been administered. It is concluded that an infusion at a rate equal to twice the maximum excretory rate and continued for two hours or longer is a rational approach to intravenuous cholangiography particularly in those patients where there has been some diffculty in bile-duct visulization.

The efficacy of meglumine ioglycamate was assessed in 100 unselected patients who underwent cholangiography for various reasons. Good to excellent opacification was achieved in 69% of all patients. A total of 17% of all patients showed side-effects, the majority of which were transient and of a minor nature. Blood pressure and liver function were apparently not affected, but SGOT levels increased transiently within 24 hours in 21% of patients. Renal excretion of the contrast medium occurred in 48% of patients, but in only 2 did it interfere with visualisation of the duct.

In the anaesthetized pig we studied the influence of the dosage of the contrast medium Iotroxinate on the following parameters of bile secretion: bile flow, bile salt excretion, concentration, and excretion of Iotroxinate. The results demonstrate that high doses of Iotroxinate inhibit the bile salt independent fraction of bile flow in a dose-dependent manner, by analogy to organic anions like Rose Bengal, Indocyaningreen, Ioglycamite. The biliary concentration of Iotroxinate however increases slightly. That means, that high doses of Iotroxinate do not impair the quality of opacification of bile ducts in x-ray examinations, as the contrast medium concentration represents the decisive parameter for a valid cholegraphy.

The effect of atropine on the bile flow and biliary excretion of ioglycamate, a biliary contrast medium, was studied on four anesthetized mongrel dogs equipped with a Thomas cannula through which the common bile duct was cannulated. With an infusion rate of 2 microgram/kg/min atropine sulphate decreased bile flow significantly. At the same time, the biliary concentration of ioglycamate was significantly increased. The biliary output of ioglycamate did not change during atropine infusion. The present study suggests that in this experimental model atropine decreases the bile flow but does not affect the excretion of ioglycamate.

Two hepatotropic contrast media in 3 different concentrations each are administered to a total of 727 patients for infusion cholecystography. It is the purpose of the study to investigate frequency of adverse reactions and quality of radiographic demonstration. In regard to tolerance, Endomirabil clearly shows advantages over Biligram. The radiologic demonstration of Endomirabil is somewhat better than with Biligram. The frequency of adverse reactions shows to be influenced by the concentration of the contrast medium as well as time of infusion, which particularly applies to Endomirabil, while in regard to the quality of visualization, ni dependence on either concentration of infusion time could be demonstrated.

The distribution and excretion of an intravenously injected, radioactive biliary contrast medium (Ioglycomate) were studied in the mini-pig after the induction of choledochal, thoracic duct and gall bladder fistulae. The investigations were carried out with free lymph and bile flow during artificial cholestasis and after occluding both ureters. Following intravenous injection of 0.24 to 1.0 ml. Bilivistan, there was a cholersis up to six times original value. Ther thoracic duct lymph showed only a small volume rise. The lymphatic circulation played no significant quantitative role in contrast distribution of Ioglycomate in the animal, nor did it influence the blood clearance curves. During normal bile flow, only 1.3% of the injected dose appeared in the thoracic duct within three hours, and during acute biliary obstruction, only 2.6%. The investigations have indicated a biliary transport maximum Ioglycomate in the mini-pig of 2.9 mg./min./kg. body weight. If the excretory capacity of the liver is exceeded and during cholestasis there is compensatory excretion of the biliary contrast medium through the kidneys.

Biliary excretion of iotroxamat (ITX) and ioglycamide (IGL) in cholecystectomized dogs fitted with a Thomas duodenal cannula is compatible with saturation kinetics exhibiting maximal excretory velocities of 2.23 +/- SD 0.18 and 1.22 +/- 0.19 mumol/min/kg, respectively. While biliary excretion of ITX obeyed classical Michaelis Menten kinetics, the data obtained with IGL suggested a more complex process. The choleretic effects of both contrast agents (23.6 +/- SD 2.29 and 25.8 +/- 2.21 microliter of excreted substance) were comparable. On the basis of these results and in view of the similar toxicity of the two contrast agents in animals, it may be expected that ITX will have advantages over IGL for intravenous cholangiography.

Previous experimenttal work in animals has shown that the hpatic excretion of iodipamide and ioglycamide is subject to a transport maximum (TM). Doses in excess of this TM are largely excreted in the urine. In the present study the TM for man was estimated in three subjects with indwelling T-tubes: figures of 19-23 mg/minute for ioglycamide were obtained. It was thought that prolonged administration of contrast at levels slightly above the TM might have advantages in patients with impaired liver function. In obstruction the gradual excretion of contrast could improve the chances of filling the ducts completely, while in hepato-cellular disease the gall bladder might have time to concentrate the contrast. Ioglycamide was therefore given by slow overnight infusion, equivalent to 35 mg/minute, to patients in whom standard cholangiography had been unsuccessful. The overall success rate was 75 per cent with similar improvement in obstructive and hepatocellular disease.

The distribution and biliary excretion of two hepatotropic contrast media, Ioglycamate and Iotroxinate, has been studied in the anaesthetized pig in infusion experiments. The new substance Iotroxinate exceeds the Ioglycamate in two of the investigated parameters: it was excreted faster and reached a higher biliary concentration. The biliary transport maximum, however, was unchanged. On the basis of these experiments the new contrast medium Iotroxinate was tested in men.

The maximum biliary excretion rate of iotroxamide was found to be significantly greater than that of iodipamide in bile-fistula dogs. High bile salt excretion rates had no effect on the rate of biliary excretion of either compound, but the choleresis associated with greater bile salt excretion reduced the biliary concentration of both agents. Both are potent choleretics, stimulating about 23.5 ml of bile per mmole of contrast agent excreted in bile. This obligatory coupling of the contrast agents with water as they are excreted in bile imposes a limit on the maximum concentration that can be achieved in bile. Since iotroxamide is excreted more rapidly in bile than iodipamide for any equimolar plasma concentration, it may be a superior contrast agent for intravenous cholangiography.

Biliary excretion of ioglycamide was studied in Wistar and Gunn rats. A hepatic transport-maximum (Tm) was observed. Higher Tm-values were found in Gunn rats, which have a greater bile flow compared to the parent Wistar rats, in spite of having a similar bile acid output. This suggests that the Tm is related to the bile acid-independent bile flow. In bile acid-depleted Wistar rats, bile acid output was 30% of control values whereas bile flow and ioglycamide-Tm had only decreased by approximately 15%. Ioglycamide excretion could not be increased by taurocholate infusion. An additional 22.0 ml of bile was excreted per mmol of biliary ioglycamide. Loads of the contrast agent markedly exceeding the Tm resulted in a decrease of its own biliary excretion and its choleretic properties. These presumed 'toxic' effects were counteracted by near-physiological amounts of taurocholate. Thus, the effect of taurocholate varies greatly depending upon the amounts of the contrast agent and the taurocholate administered.

(1) Solubilization of Telepaque in the intestine is a limiting factor in the rate of intestinal absorption. Bilopaque and Oragrafin are more water-soluble and appear to be better absorbed than Telepaque. (2) Bile salts in the intestinal lumen increase the solubility of Telepaque. Therefore, a fatty meal administered with the Telepaque is desirable to evacuate bile salts from the gallbladder into the intestine. This is not required for the more water-soluble agents, Biopaque and Oragrafin. (3) The degree of protein binding of the contrast agents can be related to the degree of toxicity. Cholografin is the most highly bound and is the most toxic. (4) Hepatic receptor proteins may specifically bind the biliary contrast agents. This may be the reason that the renal contrast materials are poorly escreted in bile compared to the biliary contrast agents. (5) Telepaque is conjugated in the liver with glucuronide making the compound more soluble in bile. This prevents precipitation of Telepaque in the gallbladder and avoids reabsorpiton from the intestine. (6) The biliary excretion of Telepaque is facilitated by bile salts. Therefore, the administration of a fatty meal with Telepaque not only increases the rate of intestinal absorption of Telepaque but also the rate of biliary excretion. (7) The rate of biliary excretion of both the oral and the intravenous contrast agents appears to be limited by a hepatic transport maximum. Above a certain dose, increased amounts of the contrast agents do not result in more rapid excretion of the agents into bile. Rapid infusion of intravenous contrast agents results in high plasma concentration and greater urinary excretion, without increasing the biliary excretion. It does not appear to be indicated in clinical practice. (8) The biliary concentration of the contrast agents used for intravenous cholangiography is determined by their rate of biliary excretion, the choleretic effect of the contrast agent, and factors that determine the rate of basal bile flow. Fixed coupling of water with the biliary excretion of these contrast agents imposes an inherent limitation on the concentration of the contrast agent in bile. It appears that the biliary concentration of the intravenous contrast materials can be increased by having the patient fast prior to intravenous cholangiography. This decreases the enterohepatic circulation of bile salts and the rate of bile-salt-dependent bile flow. (9) Failure of the gallbladder to visualize after administration of Telepaque when there is adequate biliary excretion may be due to cystic duct obstruction, failure of the inflamed gallbladder mucosa to reabosrb water, or reabsorption or the contrast agent by the diseased gallbladder mucosa. (10) Maximum concentration of Telepaque occurs at 14-19 hr after ingestion. It is at this time that radiographs of the gallbladder should be made. With Bilopaque, peak concentration occurs at 10 hr so radiographs can be made earlier when Bilopaque is used.

The binding relationships between ioglycamide and steroid hormones were determined in a liquid two-phase system with labelled ioglycamide and by direct measurement of ultraviolet light absorption. It was found that an interaction between ioglycamide and steroid hormones, particularly progesterone, existed, relative to the binding to human serum protein.