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Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

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Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

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Sodium-2-[(3-butanoylamino-2,4,6-triiodo-phenyl)methyl]butanoate

Tyropanoate Sodium
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD, vog.hin.mln.ibcn@dacim

Created: ; Last Update: June 30, 2008.

Chemical name:Sodium-2-[(3-butanoylamino-2,4,6-triiodo-phenyl)methyl]butanoateimage 49836622 in the ncbi pubchem database
Abbreviated name:Tyropanoate sodium
Synonym:Bilopaque®, WIN-8851-2, Lumopaque
Agent Category:Compound
Target:Gallbladder
Target Category:Hepatic uptake and biliary excretion after oral absorption
Method of detection:Planar X-ray, Computed Tomography (CT)
Source of signal/contrast:Iodine
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
  • Checkbox Non-primate non-rodent mammals
  • Checkbox Humans
Click on the above structure for additional information in PubChem.

Background

[PubMed]

Sodium-2-[(3-butanoylamino-2,4,6-triiodo-phenyl)methyl]butanoate (tyropanoate sodium) is an oral X-ray cholecystographic agent used to aid the radiographic visualization of the gallbladder for detecting the presence of gallstones in cholelithiasis patients (1-4). Clinically, this technique is largely superseded by ultrasound, computed tomography (CT; without contrast), and nuclear medicine techniques and is used only for selected patients (5-7). Studies in 1999-2000 reported that it might be feasible to use this class of agents with helical CT cholangiography (8).

Radiographic imaging of the gallbladder depends on the opacification of the gallbladder with an oral cholecystographic agent. Solubilization in the intestinal lumen, absorption across the intestinal mucosa, transport in the blood, uptake and excretion by the liver and final concentration of the agent in the gallbladder allow X-ray imaging of the gallbladder and the biliary tree (9-12).

Cholecystographic agents are generally weak organic acids that contain a tri-iodinated benzene ring with iodine at positions 2, 4 and 6 (2, 7, 13-16). This class of compounds includes iocetamic acid, iopanoic acid, bunamiodyl sodium and ipodate. Their major chemical differences are the different substituents at positions 1 and 3 on the aromatic ring. The hydrophobic and hydrophilic properties of these substituents determine the aqueous and lipid solubility of the compound, and it must be sufficiently lipophilic to pass through the gastrointestinal mucosa. The absence of a substituent at position 5 allows the compound to bind to serum albumin and facilitates preferential hepatocyte uptake. The exact hepatic uptake mechanism is not entirely known. The agent is then metabolized by glucuronide conjugation in the same pathway as bilirubin (17-19). These glucuronide-conjugated compounds are readily excreted into the bile, follow the bile flow to fill up the gallbladder, and then are excreted by the biliary system in the feces.

Tyropanoate sodium was first synthesized in1962 as a modification of an earlier cholecystographic agent, iopanoic acid, in an effort to decrease its toxicity (1, 15, 20). Based on the fact that aromatic amino compounds are detoxified in vivo by acetylamino groups, tyropanoate sodium was developed and was different from iopanoic acid, chiefly in the butyrylation of the amine group. Whereas iopanoic acid is insoluble in water, tyropanoate sodium as a salt is soluble in water. The greater aqueous solubility of tyropanoate sodium and the lack of effect of bile acids on its hepatic excretion favor its oral absorption in the fasting state (21).

The commercial formulation of tyropanoate sodium contains approximately 57.4% iodine for producing the necessary X-ray attenuation and organ opacification (1, 2, 4). It is no longer marketed in the United States.

Synthesis

[PubMed]

Tyropanoate sodium was synthesized by butyrylation of the amine group of iopanoic acid (20). In this method, iopanoic acid was converted to tyropanoic acid by acidifying and heating with butyric anhydride at 70-80oC for 2 hours. A yield of 84% of Tyropanoic acid was obtained, and was then converted to tyropanoate sodium by the addition of methanolic sodium hydroxide.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

No specific in vitro cell uptake or metabolic study of tyropanoate sodium has been published. In a 1982 rat liver study of the deiodination mechanism of the tyrosyl and the phenolic ring of the thyroid hormones, tyropanoate sodium was shown capable of inhibiting competitively deiodination of thyroid hormones (22). In another study using patient serum, tyropanoate sodium was also found to competitively displace thyroid hormones from serum protein binding (23)

Animal Studies

Rodents

[PubMed]

Acute toxicity studies in mice reported that the acute intravenous LD50 in mice for tyropanoate sodium was 720 mg/kg and the oral LD50 was 4.8-16.3 g/kg (20).

Other Non-Primate Mammals

[PubMed]

Preliminary imaging studies were performed in cats (20). The average cholecystographic index (ACI) using a visualization scoring scheme in cats for tyropanoate sodium (100 mg/kg) was reported to be 3.7 (13). In comparison, the ACI for iopanoic acid was 3.6.

With intravenous administration of tyropanoate sodium to dogs, the concentrations attained in the bile were approximately 60-400 times higher than the plasma concentrations (24). The urinary excretion of tyropanoate sodium was proportional to the plasma levels and accounted for about 30% of the total excretion. Both (+) and (-) enantiomers of tyropanoate glucuronide were identified in the plasma as tyropanoate sodium metabolites. Approximately 50% of the plasma tyropanoate sodium was glucuronide derivatives. In another study, the rate of biliary excretion of tyropanoate sodium was not significantly influenced by the rate of hepatic excretion of bile salts (11).

With oral administration of tyropanoate sodium to dogs, tyropanoate sodium reached a maximal iodine concentration of 11.5 ± 0.4 mg in the bile around 60 minutes after ingestion. This was higher than 2.2 ± 0.55 mg of iopanoic acid but similar to12.9 ± 1.4 mg of sodium ipodate (25). Excretion studies showed that tyropanoate sodium also caused a marked increase in bile flow (choleresis) which was not observed with iopanoate sodium (26). With the use of imaging techniques, data in dogs showed that opacification of the gallbladder might persist up to 4 days as measured by CT and up to 2.5 days by planar radiography (27). A study on the effect of diet and fasting showed no difference in mean gallbladder density measured by CT for a single dose given with a meal as compared with that in fasting. However, the density was significantly greater after a second dose when tyropanoate sodium was given in fasting (28).

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

Human biochemical studies indicated that after oral ingestion of 4.5 g of tyropanoate sodium, tyropanoate sodium was rapidly absorbed from the intestinal tract and a peak serum iodine level of 330-460 mg/liter could be reached in 1-4 h (14, 15). Approximately 50% of tyropanoate sodium was excreted in the urine and 50% in the feces. In normal subjects, the gallbladder was optimally opacified 5-8 h after ingestion of tyropanoate sodium (29). The simultaneous administration of a meal with tyropanoate sodium appeared to impair gallbladder opacification (30). The effective absorbed dose for a typical cholecystography was reported to be about 2 mSv (200 mrem) (31). In comparison, the effective dose for a typical CT scan was estimated to be 8.8 mSv (880 mrem).

In patient studies with a 3 g dose of tyropanoate sodium, the time of peak visualization of the gallbladder with planar radiography after oral ingestion was 8-10 h (82-98% of 54 patients), whereas iopanoic acid could take 14-19 h (32, 33). In 13 patients with acute pancreatitis, the mean plasma level of tyropanoate sodium was 0.329 µmol/ml in 1-6 h compared with 0.061 µmol/ml for iopanoic acid (34).

In a retrospective study of 364 patient cases, the clinical performance of gallbladder visualization of tyropanoate sodium (4.5 g) appeared to be comparable to that of iopanoic acid (3 g) with fewer side effects (24.3% side effects for tyropanoate sodium and 48.7% side effects for iopanoic acid) (1). Another crossover comparison study of 50 patients who received both agents in 2 weeks reported improvement in gallbladder visualization for tyropanoate sodium (70% good visualization for tyropanoate sodium and 58% for iopanoic acid) with similarly fewer side effects (4). In 50 patients with acute alcoholic pancreatitis, 31% of the tyropanoate sodium (3 g) group achieved diagnostic single-dose cholecystograms, compared with only 11% of the iopanoic acid (3 g) group (34).

References

1.
Benisek G.J., Gunn J.A. A preliminary clinical evaluation of a new cholecystographic medium bilopaque. Am J Roentgenol Radium Ther Nucl Med. 1962;88(4):792–796. [PubMed: 13867240]
2.
Marshall T.R. Clinical comparison of locetamic acid, lopanoic acid and tyropanoate sodium. J Indiana State Med Assoc. 1976;69(10):742–3. [PubMed: 135811]
3.
Pollack S. Clinical evaluation of a new cholecystographic agent: WIN 8851-2 (Bilopaque) Oklahoma State Medical Association. 1963;56:13–17. [PubMed: 13971989]
4.
Burhenne H.J. Bilopaque: A new cholecystographic medium. Radiology. 1963;81:629–631. [PubMed: 14078329]
5.
Fiske S.A., Stamper D.W. The use of calcium Oragrafin granules in repeat cholecystography, with supplemental ultrasonographic evaluation. J Am Osteopath Assoc. 1984;83(7):512–5. [PubMed: 6706718]
6.
Noguchi K., Suzuki H., Nakahata M., Kurosawa S., Nakagawa S. Prolonged treatment of hyperthyroidism with sodium tyropanoate, an oral cholecystographic agent: a re-evaluation of its clinical utility. Clin Endocrinol (Oxf) 1986;25(3):293–301. [PubMed: 3791669]
  • 7. Swanson, D.P., S.M. Simms, Cholecystographic and cholangiographic contrast media, in Pharmaceuticals in Medical Imaging, D.P. Swanson, H.M. Chilton and J.H. Thrall, Editor. 1990, MacMillan Publishing Co., Inc.: New York. p. 184-220.
  • 8.
    Chopra S. K.N.C., K. Ramakrishna, H. Rhim and G.D. Dodd, Helical CT cholangiography wiht oral cholecystographic contrast material. Radiology. 2000;214:596–601. [PubMed: 10671618]
    9.
    Amberg J.R., Thompson W.M., Golberger L., Williamson S., Alexander R., Bates M. Factors in the intestinal absorption of oral cholecystopaques Invest Radiol 198015Suppl6S136–41. [PubMed: 7203915]
    10.
    Berk R.N., Loeb P.M. Pharmacology and physiology of the biliary radiographic contrast materials. Semin Roentgenol. 1976;11(3):147–56. [PubMed: 133461]
    11.
    Berk R.N., Loeb P.M., Cobo-Frenkel A., Barnhart J.L. The biliary and urinary excretion of sodium tyropanoate and sodium ipodate in dogs: pharmacokinetics, influence of bile salts and choleretic effects with comparison to iopanoic acid. Invest Radiol. 1977;12(1):85–95. [PubMed: 838560]
    12.
    Janes J.O., Dietschy J.M., Berk R.N., Loeb P.M., Barnhart J.L. Determinants of the rate of intestinal absorption of oral cholecystographic contrast agents in the dog jejunum. Gastroenterology. 1979;76(5 Pt 1):970–7. [PubMed: 155546]
    13.
    Hoppe J.O., Archer S. Observations on a series of aryltriiodoalkanoic acid derivatives with particular reference to a new cholecystographic medium, Telepaque. American Journal of Radiology. 1953;79:631–637. [PubMed: 13030919]
    14.
    Davis J.J. Tyropanoate Sodium. A New Oral Cholecystographic Medium. Rocky Mt Med J. 1964;61:35–9. [PubMed: 14137928]
    15.
    Judkins M.P., Billimoria P.E., Dotter C.T. A comparative evaluation of a new oral cholecystographic agent bilopaque with orabilex. Am J Roentgenol Radium Ther Nucl Med. 1963;89:859–863. [PubMed: 14042043]
    16.
    Wishart D.L., Dotter C.T. Comparison of the opacifying characteristics and pharmacologic responses of iocetamic acid (Cholebrine), a new oral cholecystographic agent, with sodium tyropanoate (Bilopaque) Am J Roentgenol Radium Ther Nucl Med. 1973;119(2):429–32. [PubMed: 4748234]
  • 17. Loeb, P.M., R.N. Berk, Biliary contrast materials, in Radiology of the gallbladder and bile ducts, R.N. Berk, A.R. Clemett, Editor. 1977, W.B. Saunders Co.: Philadelphia. p. 71-100.
  • 18.
    McChesney E.W. a.J.O.H., Observations on the absorption and excretion of the glucuronide of iopanoic acid in the cat. Arch Int Pharmacodyn Ther. 1956;105:306–312. [PubMed: 13314738]
    19.
    Muhletaler C.A., Gerlock A.J., Amberg J.R., Avant G.R. Radiographic appearance of the nonabsorbed (unconjugated) and conjugated sodium tyropanoate (bilopaque) in the bowel. Invest Radiol. 1982;17:506–509. [PubMed: 7141832]
    20.
    Hoppe J.O., Ackerman J.H., Larsen A.A., Moss J. Sodium tyropanoate, a new oral cholecystographic agent. Journal of Medicinal Chemistry. 1970;13(5):997–999. [PubMed: 5458405]
    21.
    Longstreth G.F., Slivka J. Tyropanoate cholecystography early in the course of acute pancreatitis J Clin Gastroenterol 19813Suppl 147–50. [PubMed: 7328298]
    22.
    Fekkes D., Hennemann G., Visser T.J. Evidence for a single enzyme in rat liver catalysing the deiodination of the tyrosyl and the phenolic ring of iodothyronines. Biochem J. 1982;201(3):673–6. [PMC free article: PMC1163699] [PubMed: 7092818]
    23.
    Felicetta J.V., Green W.L., Huber-Smith M.J. Effects of cholecystographic agents and sulfobromophthalein on binding of thyroid hormones to serum proteins. J Clin Endocrinol Metab. 1983;57(1):207–12. [PubMed: 6853679]
    24.
    Cooke W.J., Cooke L.M. Biliary and urinary excretion of tyropanoic acid and its Metabolites in the dog. Invest Radiol. 1983;18(3):285–92. [PubMed: 6618819]
    25.
    Menuck L., Amberg J.R., Bates M. Hepatic excretion of cholecystopaques introduced into the canine jejunum. Invest Radiol. 1977;12(1):106–8. [PubMed: 138663]
    26.
    Nelson J.A., Straubus A.E., Amberg J.R. The choleretic action of sodium tyropanoate (bilopaque sodium) in the dog: preliminary observation. Invest Radiol. 1974;9(6):438–43. [PubMed: 4430583]
    27.
    Hunter T.B., Fon G.T., Berk R.N., Capp M.P. Concentration and excretion of contrast agents during oral cholecystography as measured by computed tomography in dogs. Gastrointest Radiol. 1981;6(4):349–52. [PubMed: 7308718]
    28.
    Fon G.T., Hunter T.B., Berk R.N., Capp M.P. The effect of diet and fasting on gallbladder opacification during oral cholecystography in dogs as measured by computed tomography. Radiology. 1980;136(3):585–92. [PubMed: 7403534]
    29.
    Muhletaler C.A., Gerlock A.J., Amberg J.R., Avant G.R. Radiographic appearance of the nonabsorbed (unconjugated) and conjugated sodium tyropanoate (Bilopaque) in the bowel. Invest Radiol. 1982;17(5):506–9. [PubMed: 7141832]
    30.
    Loeb P.M., Berk R.N., Janes J.O., Perkin L., Moore J. The effect of fasting on gallbladder opacification during oral cholecystography: a controlled study in normal volunteers. Radiology. 1978;126(2):395–401. [PubMed: 341220]
    31.
    Ron E. Cancer risks from medical radiation. Health Phys. 2003;85(1):47–59. [PubMed: 12852471]
    32.
    Oliphant M., Whalen J.P., Evans J.A. Time of optimal gallbladder opacification with bilopaque (tyropanoate sodium) Radiology. 1974;112(3):531–2. [PubMed: 4843281]
    33.
    Han S.Y., Witten D.M. Clinical trial of bilopaque (tyropanoate sodium) oral cholecystography. Evaluation of time for the optimal and peak opacification of the gallbladder. Radiology. 1974;112(3):529–30. [PubMed: 4843280]
    34.
    Smith H.J., Corbett D.B., Loeb P.M., Peterson W.L. Oral cholecystography in the early phase of acute alcoholic pancreatitis. A prospective, randomized comparison of Telepaque and Bilopaque. Invest Radiol. 1982;17(6):629–33. [PubMed: 6759457]
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