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Because of relatively low acute toxicity, iosulamide meglumine has been recommended as an improved contrast material for intravenous cholangiography. It has been postulated that high doses of the compound could be given safely with the expectation of achieving greater biliary excretion and improved opacification of the biliary tree. Experiments performed in dogs show that higher rates of infusion of iosulamide result in greater urinary elimination without additional biliary excretion. Consequently, iosulamide is unlikely to have any special advantage as a contrast agent.

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.

To determine the rational for the ability of glucagon to enhance opacification of the bile ducts during intravenous cholangiography, which has been claimed in recent clinical reports, experiments were performed in dogs which had had Thomas cannulas inserted. A constant step-wise infusion of iodipamide was administered with or without a bolus injection and constant infusion of glucagon. At every infusion rate of iodipamide the biliary concentration of the contrast agent was less when glucagon was administered. Glucagon caused a choleresis, but had no effect on the rate of excretion of iodipamide. It is concluded that the theory that glucagon is of value to improve opacification of the bile ducts during intravenous cholangiography is unlikely to be confirmed by further clinical trials.

A new zwitterionic iodinated molecule, 2-[3-(N-ethyl-2-hydroxyethyl) amino-acetamido-2, 4, 6-triiodobenzyl]-butyric acid (RCK-136) was synthesized, and its potential as an oral cholecystopaque was tested. In rats, 15 minutes following intravenous injection, RCK-136 reached maximum biliary concentration; 84% of the dose was excreted into bile. Biliary excretion of RCK-136 elicited a strong choleresis (44 ml of bile flow per mmol compound). Intravenous LD50 in rats averaged 390 mgI/kg. ED50 in rats, intradiencephalic, averaged 1.98 mgI/kg. The average densities of cholecystograms produced in three dogs with iosumetic acid and/or RCK-136 were comparable.

The biliary and urinary excretion of sodium tyropanoate (Bilopaque) and sodium ipodate (Oragrafin) were studied in unanesthetized bile-fistula dogs using stepwise, increasing, intravenous infusions of the contrast materials. A constant intravenous infusion of sodium taurocholate was administered at the rate of either 0.5 or 2.0 mu moles per min per kg throughout each experiment. The biliary excretion of sodium tyropanoate or sodium ipodate was not effected by the rate of sodium taurocholate infusion. The maximum rate of biliary excretion of sodium ipodate was significantly greater than that of sodium tyropanoate with the low taurocholate infusion, but there was no significant difference between the two with the high taurocholate infusion. With the low taurocholate infusion the maximum biliary excretion rate of sodium tyropanoate (0.956 mu moles per min per kg) and sodium ipodate (1.472 mu moles per min per kg) were significantly greater than the maximum biliary excretion of iopanoic acid (Telepaque) (0.671 mu moles per min per kg). With the high taurocholate infusion the maximum biliary excretion rates of the three contrast agents were not statistically different. Both sodium tyropanoate and sodium ipodate produced an increase in canalicular bile flow (8-11 ml per millimole). These data suggest that in clinical cholecystography sodium tyropanoate and sodium ipodate are not excreted in bile more rapidly than iopanoic acid, except when the rate of biliary excretion of bile salts is low; that is, except in patients who are fasting or those who are on a fat-free diet.

The hepatic excretion of radiographic contrast materials has a major impact on the composition and volume of bile. One obvious effect is the presence of the contrast agent in bile at a concentration that is determined by the rate of hepatic excretion, the rate of basal bile flow, and the rate of bile flow induced by the biliary excretion of the contrast agent. The magnitude of the choleretic response associated with the biliary transfer of contrast materials varies over a wide range. Iopanoic acid does not increase bile flow, whole RCK-136, an experimental contrast material that is similar to iopanoic acid chemically (both are triiodophenyl alkanoates), is a potent choleretic, generating 44 microliter of bile for each mumol excreted into bile. In distinction, the contrast materials in another chemical class, the dimers of triiodobenzoic acid, increase bile flow, but over a narrow range (20-25 microliter/mumol). The changes in bile flow and composition accompanying the administration of iodoxamate, one of the compounds of the dimer type, were compared to the choleresis induced by taurocholate. The additional bile flow was canalicular in origin in both instances, but the electrolyte composition of the bile was different. Bicarbonate concentration in the iodoxamate-induced increment of bile was nearly twice the concentration of bicarbonate in bile stimulated by taurocholate (52.3 and 25.3 mEq/1, respectively). This suggests a canalicular mechanism for iodoxamate-stimulated bicarbonate entry into the bile. The characteristics of bile induced by iodoxamate were also compared to bile associated with a variety of other choleretic agents, including diethyl maleate, DBcAMP, SC2644, and secretin. Only SC2644 stimulated canalicular bile flow with a high bicarbonate concentration similar to iodoxamate.

The extent to which various concentrations of the paramagnetic metal ions [gadolinium (III), manganese (II), chromium (III), iron (III), nickel (II), copper (II), and cobalt (II)] affect proton magnetic relaxation times of distilled water, 4% human serum albumin (HSA), and dog plasma was studied in vitro. The pH of water and HSA varied from 4 to 8. Nuclear magnetic resonance relaxation parameters, T1 and T2, were measured at 10.7 MHz using inversion recovery and spin-echo radiofrequency sequences, respectively. The presence of Mn(II), Gd(III) and Cr(III) in water significantly reduced T1, while Fe(III), Ni(II), Cu(II) and Co(II) had only a minimal effect. In 4% HSA and dog plasma Mn(II) and Cu(II) had the greatest effect on T1. At neutral pH, Gd(III) and Cr(III) had little effect on T1, while Mn(II) induced a large shortening of T1. All of the metal ions changed T2 less than T1. These differences in proton relaxation enhancement caused by the various ions in the three solutions studied are due to variations in the effective magnetic moment, the degree of binding of the ions to protein, and the chemical form of the ion associated with changes in pH. Thus, it is impossible to predict the effect of metal ions on proton relaxation in vivo based solely on in vitro studies, because of the complexity of various biologic fluids in vivo.

The biliary excretion of two oral cholecystographic contrast agents, iocetamic acid and iopanoic acid, were compared during low and high taurocholate infusion rates. The pharmacokinetics of these compounds after intravenous infusion were studied in bile-fistula dogs using both indirect and direct pharmacokinetic techniques. The indirect multiple infusion technique, corrected for urinary excretion, provides a reliable estimate of the maximum biliary excretion rates of either contrast agent without necessitating the sampling of biliary output. The results indicate that taurocholate facilitates the biliary excretion of both agents. At both taurocholate infusion rates studied, the maximum biliary excretion rate of iocetamic acid is greater than that of iopanoic acid.