Prolonged treatment of hyperthyroidism with sodium tyropanoate, an oral cholecystographic agent: a re-evaluation of its clinical utility.

To re-evaluate the clinical utility of the prolonged management of hyperthyroidism with sodium tyropanoate (TP), an oral cholecystographic agent, we studied the changes in the scoring of thyrotoxic signs and symptoms (thyrotoxic index; TI), serum concentrations and binding of thyroid hormone, and circulating TSH receptor antibodies (TRAb) in two groups of patients with Graves' disease; seven patients (TP group) received TP (1.5 g daily) alone for 14 weeks, and six patients (TP + MMI group) received methimazole (MMI; 30 mg daily) in addition to TP for 8 weeks and MMI alone thereafter. In the TP group, the TI reduced significantly, but it failed to reach a euthyroid level in all except one. Serum total T4 (TT4), free T4 (FT4), and T3 uptake (T3U) values declined by the third week of treatment, but an 'escape' occurred thereafter. Serum rT3 and T4 binding globulin (TBG) levels were increased. The TRAb titres were increased slightly but significantly. Serum T3 levels fell within a week but remained higher than normal during the treatment. In the TP + MMI group, all patients achieved a normal TI by the end of the treatment. Serum TT4, FT4 and T3U fell more significantly than those in the TP group, indicating no escape from the effect of TP. The serum TRAb decreased significantly. Serum T3 levels showed a greater reduction than those in the TP group, and remained decreased even after withdrawal of TP. In a further 9 patients receiving TP alone for 4-14 weeks (7.3 +/- 5.0 weeks on the average), TP was withdrawn and replaced by MMI.(ABSTRACT TRUNCATED AT 250 WORDS)

Cholecystographic agents and sulfobromophthalein inhibit the binding of L-thyroxine to plasma membranes of rat hepatocytes.

Cholecystographic agents and sulfobromophthalein (BSP) cause a major discharge of labeled T4 from the liver in man in vivo. In the present study we sought to determine if this discharge is partially due to inhibition of T4 binding to plasma membrane sites. Plasma membranes were isolated from hepatocytes of female Sprague-Dawley rats, and 5'-nucleotidase levels were measured to demonstrate plasma membrane viability. Specific binding of T4 (Ka, 1.01 X 10(8) M) was confirmed by displacement of labeled T4 by unlabeled hormone (10(-10)-10(-5) M). Displacement of labeled hormone was also produced by addition of tyropanoate, iopanoate, ipodate, or BSP. At 5-mM concentrations of inhibitor, the Ka for T4 declined to 4.00 X 10(7) M with BSP, 5.07 X 10(7) M with ipodate, 5.62 X 10(7) M with tyropanoate, and 7.43 X 10(7) M with iopanoate. Thus, a portion of the discharge of hepatic T4 after administration of these agents may be due to competitive inhibition of binding to plasma membrane sites.

Clinical significance of presence of the conjugated bilopaque in the bowel after oral cholecystography

Oral cholecystogaraphy after ingestaion of the 3.0 gr. Sodium tyropanoate (Bilopaque) was done in 504 patiens from Jan. 1983 to Aug. 1983. Simple supine views of the abdomen of 37 patient, in whom the gall bladder was eithrer nonvisualized or faintly visualized upto 17 houurs after Bilopaque administration, were reviewed in search of the presence of conjugatd material in the bowel. The results were as follows; 1. The ratio of male to female was nearly 2:3, and age distribution was even from 20 years to 79 years. 2. Among 26 cases which showed conjugated Bilopaque in the bowel, cholecystitis with stoens was 20 cases(77% and acalculus cholecystitis was 6 cases(23%).3. Among 11 cases which showed no conjugated Bilopaque in the bowel hepatitis was 3 cases (28%) and clonorchis sinensis, salmonellosis, pancreatitis, acute gastrities was 2 cases (13%) respectively. 4. All of the 20 cases of cholecystitis with stone showed conjugated Bilopaque in the bowel. 5. Among 6 cases of which conjugated Bilopaquein the bowel, salmonellosis was 1 case(17%) and remaining 5 cases (83%) were acalculus cholelcystitis. 6. The results of our study show that the presence of conjugated Bilopaque in the bowel in nonvisualized or faintly visualized gall bladder after oral cholecystography is of definite indicative of cholecystitis. 7. Surgical intervention or ultrasonographic examination of the gall bladder without double dose or second dose oral cholecystography on such cases is recommended.

Effects of cholecystographic agents and sulfobromophthalein on binding of thyroid hormones to serum proteins.

A number of interactions between thyroid hormones and cholecystographic agents have previously been demonstrated. In the present study we show that cholecystographic agents also interfere with the binding of thyroid hormones to serum proteins. A commercial kit (Tri-Tab) was used in which the uptake of labeled hormone from serum by a silicate adsorbent tablet is measured. In the presence of cholecystographic agents or sulfobromophthalein (BSP), the amount of labeled hormone bound to adsorbent increased in a dose-dependent fashion, reflecting displacement from protein-binding sites. The order of potency was BSP greater than ipodate greater than iopanoate greater than tyropanoate. Displacement of hormone was confirmed by a second methodology in which graded amounts of unlabeled T4 were added to the system. This allowed a Scatchard analysis to be performed for binding sites on T4-binding globulin. The cholecystographic agents and BSP caused displacement of the Scatchard slopes, again demonstrating interference with binding to serum protein sites. A method is described in which the change in Scatchard slope produced by an inhibitor is employed to compute the association constant between T4-binding sites on T4-binding globulin and the inhibitors. The values were: BSP, 14.6 X 10(3) M-1; ipodate, 4.7 X 10(3) M-1, iopanoate, 2.2 X 10(3) M-1; and tyropanoate, 0.1 X 10(3) M-1. Because of these relatively low values and the rapidity with which these agents are normally cleared from serum, it seems likely that effects on free hormone levels would be transient and of small magnitude during routine cholecystography. Also, ipodate, in the 1 g/day dose that has been employed experimentally to treat hyperthyroidism, should have a negligible effect on protein binding. On the other hand, when high levels of these compounds are used in experimental settings to study other aspects of thyroid hormone metabolism, changes in protein binding can occur and confound interpretation of results.

Biliary and urinary excretion of tyropanoic acid and its Metabolites in the dog.

The biliary and urinary excretion of tyropanoate-derived material was studied in the anesthetized dog with various plasma levels of tyropanoate. Bile, plasma, urine, and hepatic tissue were analyzed by high-pressure liquid chromatography for the presence of tyropanoate, enantiomers of tyropanoate glucuronide, and other typropanoate metabolites. Approximately 90% of the material secreted in the bile was in the form of tyropanoate glucuronide, equally distributed between (+)- and(-)-tyropanoate glucuronide, and approximately 10% was excreted as other tyropanoate-derived metabolites. It is suggested that the choleretic effect associated with the excretion of tyropanoate is associated with the nonglucuronide metabolites. Tyropanoate itself was not secreted into bile. In plasma, approximately 40% of the material was tyropanoate, while approximately 50% existed as tyropanoate glucuronide and 10% as other tyropanoate metabolites. The plasma concentration of (-)-tyropanoate glucuronide was significantly greater than that of (+)-tyropanoate glucuronide. The urinary excretion of tyropanoate-derived material accounted for up to 35% of the total excretion. The primary metabolite in urine was tyropanoate glucuronide. Tyropanoate accounted for less than 5% of the material in urine, whereas other tyropanoate metabolites contributed approximately 20%. The data suggest that there is a stereoselective disposition of tyropanoate metabolites that may influence the overall disposition of the compound.

Oral cholecystography in the early phase of acute alcoholic pancreatitis. A prospective, randomized comparison of Telepaque and Bilopaque.

Biliary tract disease is a major cause of acute pancreatitis. However, with traditionally employed Telepaque, radiographic visualization of the gallbladder during acute pancreatitis remains unreliable, even in patients with apparently normal gallbladders. Therefore, oral cholecystography has customarily been deferred for such patients for several weeks. Recently, successful oral cholecystography has been described during the acute episode of pancreatitis, using Bilopaque, a more water-soluble cholecystopaque. The relative intestinal absorption of Telepaque and Bilopaque and the ability of these agents to produce diagnostic oral cholecystograms of fasting patients with acute alcoholic pancreatitis were compared. Forty-five hospitalized patients were studied within 96 hours of admission. Mean peak plasma contrast concentrations for Bilopaque exceeded those for Telepaque. Thirty-one percent of the Bilopaque group achieved diagnostic single-dose oral cholecystograms, compared with to 11% of the Telepaque group (P less than 0.05).

Radiographic appearance of the nonabsorbed (unconjugated) and conjugated sodium tyropanoate (Bilopaque) in the bowel.

A series of abdominal radiographs were taken in eight normal volunteers after the ingestion of sodium tyropanoate (Bilopaque). These showed nonabsorbed sodium tyropanoate to have a granular appearance, while the conjugated form had a smooth homogeneous appearance. The appearance of conjugated sodium tyropanoate in the bowel has the same diagnostic significance as conjugated iopanoic acid in the presence of a nonvisualized gallbladder. It indicates that the contrast material has passed through the hepatic ductal system and that there has been an opportunity for the gallbladder to opacify.

A clinical trial of oral cholecystography using combinations of contrast agents and two consecutive doses.

Fifteen healthy volunteers underwent a randomized trial of oral cholecystography (OCG) using 5 different combinations of contrast agents given as 2 consecutive doses: Telepaque (iopanoic acid) given with food (TF) or without food (T), Bilopaque (sodium tyropanoate) given without food, and a combination of both agents (TF-B). The density of gallbladder opacification was judged visually on a scale of 1+ to 4+ and quantitatively by a densitometric method. Comparison of gallbladder opacification on the first and second days of the study revealed 52 of 75 (70%) combinations (TF-T, TF-TF,T-T, TF-B, B-B) resulted in improved opacification, 17% in equal opacification, and 13% in worse opacification on day 2. The TF-B combination showed the highest number (9) of excellent (grade 4+) results and the lowest number (2) of poor (grade 1+ and 2+) results, gave the best opacification in 8 volunteers, and had the highest average density difference (0.32) between first- and second-day opacifications. The TF-TF combination was the next most effective, and the T-T combination was the least effective. The results indicate that OCG in 2 consecutive doses is superior to single-dose OCG, and that a combination of TF-B or TF-TF will provide the greatest gallbladder opacification. The TF-B combination is recommended because of better patient tolerance.

Subjective vs. objective evaluation of gallbladder opacification during oral cholecystography in comparative clinical trials: implications for studies involving visual assessment.

Radiographs and CT images taken during oral cholecystography in dogs were interpreted in an independent, blind fashion by three radiologists on two occasions and visual assessment of gallbladder density compared to the actual CT values. While there was significant intra- and inter-observer variation, the mean scores for the observers' interpretations of both radiographs and prints correlated well with the actual CT values (p less than 0.05). In five out of six comparisons between first and second readings, the observers gave a lower score on the second reading. The considerable variation reflects the problems inherent in subjective evaluation of agents that produce small but measurable differences in radiographic density. Studies involving such subjective data have to be carefully designed in order to obtain meaningful results.

Evidence for a single enzyme in rat liver catalysing the deiodination of the tyrosyl and the phenolic ring of iodothyronines.

The enzymic 5'-deiodination of 3',5'-di-iodothyronine and 5-deiodination of 3,3',5-tri-iodothyronine by rat liver microsomal fractions were found to be characterized by apparent Km values of 0.77 and 17.4 microM respectively, 3',5'-Di-iodothyronine was a competitive inhibitor of 3,3',5-tri-iodothyronine 5-deiodination (Ki 0.65 microM) and 3,3',5-tri-iodothyronine was a competitive inhibitor of 3',5'-di-iodothyronine 5'-deiodination (Ki 19.6 microM). In addition, several radiographic contrast agents and iodothyronine analogues inhibited both reactions competitively and with equal potencies (r = 0.999). These results strongly suggest the existence of a single hepatic deiodinase acting on both the tyrosyl and phenolic ring of iodothyronines.

Conjugated sodium tyropanoate (Bilopaque) in the bowel: significance of its presence or absence after first-dose oral cholecystography.

Oral cholecystography following the ingestion of 4.5 g of sodium tyropanoate (Bilopaque) was performed in 1,053 patients. The radiographs of 89 patients in whom the gallbladder was either faintly visualized or nonvisualized were reviewed for the presence of conjugated contrast material in the bowel. All 89 of these patients underwent second-dose cholecystography. Oral cholecystography was found to be 100% accurate in the diagnosis of gallbladder disease when conjugated contrast media was found in the bowel in the presence of a faintly visualized or nonvisualized gallbladder. When this combination of findings is seen on the first-dose examination, a second-dose examination is unnecessary. When no conjugated contrast material is seen in the bowel after a first dose, a second dose is helpful only in those patients with normal biochemical liver function tests.

Tyropanoate cholecystography early in the course of acute pancreatitis.

Oral cholecystography (OCG) has traditionally been delayed until several weeks after hospitalization for pancreatitis because of the putative frequent poor visualization during the acute episode. Recently, OCG with iopanoic acid was reported successful in most patients with acute pancreatitis soon after resumption of a solid diet. We evaluated OCG with sodium tyropanoate, a pharmacokinetically different contrast material, in 30 hospitalized patients with pancreatitis before resumption of solid food. It accurately evaluated the gallbladder in 24 cases (80%). Abnormal liver function tests, including mild hyperbilirubinemia, did not interfere with the examination. Consequently, 1) tyropanoate OCG adequately opacifies the gallbladder in most patients with acute pancreatitis who are fasting or taking liquids only; 2) allows gallbladder evaluation earlier than with iopanoic acid OCG; 3) is less affected by hepatic dysfunction; and 4) provides an alternative to ultrasonography.

Concentration and excretion of contrast agents during oral cholecystography as measured by computed tomography in dogs.

Nine healthy mongrel dogs were given 2 consecutive doses of 1 of 3 cholecystographic contrast agents (iopanoic acid, sodium ipodate, and sodium tyropanoate), followed by daily computed tomograms (CT) and abdominal radiographs in a randomized crossover study in order to determine: (a) the maximum time for excretion of the contrast material from the gallbladder, (b) the maximum time for elimination of contrast material from the blood, and (c) the correlation between the density of the gallbladder on CT and the actual concentration of iodine in the gallbladder bile. In all 9 animals gallbladder opacification disappeared on CT within 4 days after administration of the contrast material. Plain abdominal radiographs did not show gallbladder opacification after 2 1/2 days. Daily blood iodine measurements showed that all of the contrast material was cleared from the blood within 7 days after administration. In 7 dogs CT imaging of the gallbladder was followed by percutaneous aspiration of bile from the gallbladder using CT guidance. There was a direct linear correlation between the actual concentration of iodine in the bile and the density of the gallbladder on CT (r = 0.925). This suggests that CT measurements can be used to determine the concentration of contrast agents in the gallbladder during oral cholecystography.

Factors in the intestinal absorption of oral cholecystopaques.

Interest in the pharmacokinetics of cholecystopaques initially centered on transport from blood to bile. The data obtained in this effort have been valuable and have shown that the maximal iodine concentration achievable in the bile is quite similar for all of the currently available compounds. This concentration is, of course, dose dependent. the transport of contrast material from the bowel to the blood has been shown to be quite variable. Considerable progress was made in understanding this. The tremendous differences in absorption of iopanoic acid depending upon the pH of the administered solution was an initial revelation. The development of the concept that there is a water layer through which the cholecystopaque must pass before reaching the lipid membrane of the intestinal cell has added clarity to understanding the difference in absorption between water-soluble and water-insoluble cholecystopaques. A complete knowledge of what might enhance or inhibit absorption is not known. There is beginning to be an understanding of how intestinal dose relates to plasma levels. This should lead to an optimal dose-timing scheme for each cholecystopaque. The basic assumption is that the highest iodine concentration in the gallbladder leads to the most accurate cholecystography. If this is true, the gallbladder needs to be offered bile at the maximum concentrations during the period preceding filming. To accomplish this, the appropriate plasma level necessary for maximum excretion is needed. Experimental data suggest that our current clinical methods in regard to dose and dose timing need revision to optimize cholecystography. This revision needs to take place with a careful look at toxicity. Accepting the present premise that oral cholecystography can be improved, perhaps without a significant increase in morbidity, a fundamental question to be asked is: is it worth it?

The effect of diet and fasting on gallbladder opacification during oral cholecystography in dogs as measured by computed tomography.

To determine the influence of diet and fasting on gallbladder opacification during oral cholecystography, 10 dogs were studied in a blind, random fashion, giving single or two consecutive doses of iopanoic acid, sodium tyropanoate, or sodium ipodate while the animals were fasting, on a normal diet, or on a low-fat diet. Gallbladder density was determined by CT to eliminate the bias created by subjective interpretation of radiographs. For maximum, first-dose gallbladder opacification during clinical cholecystography, iopanoic acid should be given with a meal and sodium ipodate while the patient is fasting; diet makes no difference with sodium tyropanoate. For maximum opacification with two consecutive doses, iopanoic acid may be given with a meal or during fasting, while sodium ipodate and sodium tyropanoate should be administered during fasting.

Inhibition of hepatic binding of thyroxine by cholecystographic agents.

Subsequent to studies indicating that cholecystographic agents and sulfobromophthalein (BSP) inhibit uptake of thyroxine (T(4)) by rat liver slices, the effect of such compounds on hepatic storage of T(4) in man has been examined. After intravenous administration of [(125)I]T(4) to five normal subjects, hepatic radioactivity, estimated by external gamma counting, rose to a peak in approximately 4 h and then declined in parallel with serum radioactivity. When a 6-g dose of the cholecystographic agent, tyropanoate (Bilopaque), was administered orally 3 d later, estimated hepatic extravascular radioactivity fell 50-60% within 4 h and then rose toward the pretyropanoate value. Concomitant with the fall in hepatic radioactivity, serum radioactivity rose 57-70%, as did stable T(4) levels in serum, suggesting that hormone discharged from the liver entered the serum. Both uptake of T(4) and discharge by tyropanoate were much less in two patients with liver disease. Ipodate (Oragrafin), 12 g orally in two subjects, caused much smaller changes in hepatic and serum radioactivity. However, ipodate also caused a doubling of the percent free T(4) in the serum as judged by equilibrium dialysis, and the ratio of hepatic radioactivity to free [(125)I]T(4) in serum declined markedly after ipodate, similar to the fall in hepatic:serum (125)I ratios after tyropanoate. BSP, 20 mg/kg i.v. in three subjects, caused a smaller change; the decline in hepatic T4 content averaged 19%. We conclude that these organic anions, tyropanoate, ipodate, and BSP, all can displace T(4) from the liver. The results imply a link between T(4) transport and organic anion transport, and indicate a mechanism for altering hepatic T(4) content in man that could be the site of physiologic regulation or of disease. A method is described whereby analysis of the change in hepatic and plasma radioactivity after tyropanoate could be employed to estimate hepatic T(4) content in diverse clinical circumstances.

Determinants of the rate of intestinal absorption of oral cholecystographic contrast agents in the dog jejunum.

Successful opacification of the gallbladder during oral cholecystography depends on adequate absorption of the contrast agent from the intestine. The present studies were undertaken to define the specific characteristics of the intestinal mucosa and the properties of the various contrast agents which determine their rates of intestinal absorption. The polarity of the compounds was established by determining the ratios of their distribution between bulk solvents (benzene and water). In addition, the maximum aqueous solubility of each compound was determined. Using in vivo cannulated segments of dog jejunum, apparent passive permeability coefficients were measured. From these data, the apparent maximal rate of intestinal absorption was calculated. The six cholecystopaques studied differed markedly in polarity as judged by their varying ratios of distribution between benzene and water. The permeability coefficients varied inversely with the polarity of the compounds. However, the incremental changes in the coefficients were considerably less than the corresponding changes observed in the partition ratios. The rates of absorption of the more polar contrast agents (tyropanoate, iopronic acid, and iocetamic acid) were greater than the less polar compounds (iopanoic acid, sodium ipodate, and calcium ipodate) under the conditions in which the resistance of the unstirred water layer is not rate limiting and where bile acid micelles are not present.